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WO1999036393A1 - INHIBITEURS DE L'ADHESION CELLULAIRE A MEDIATION PAR α4 - Google Patents

INHIBITEURS DE L'ADHESION CELLULAIRE A MEDIATION PAR α4 Download PDF

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Publication number
WO1999036393A1
WO1999036393A1 PCT/US1999/000993 US9900993W WO9936393A1 WO 1999036393 A1 WO1999036393 A1 WO 1999036393A1 US 9900993 W US9900993 W US 9900993W WO 9936393 A1 WO9936393 A1 WO 9936393A1
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WO
WIPO (PCT)
Prior art keywords
group
substituted
lower alkyl
phenyl
halogen atom
Prior art date
Application number
PCT/US1999/000993
Other languages
English (en)
Inventor
Ila Sircar
Kristjan S. Gudmundsson
Richard Martin
Original Assignee
Tanabe Seiyaku Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2000540111A priority Critical patent/JP3634749B2/ja
Priority to IL13738599A priority patent/IL137385A0/xx
Priority to SG200204434A priority patent/SG118147A1/en
Priority to AU24584/99A priority patent/AU749568B2/en
Priority to CA002318527A priority patent/CA2318527C/fr
Priority to NZ506081A priority patent/NZ506081A/xx
Priority to EP99904115A priority patent/EP1049662B1/fr
Priority to DE69932032T priority patent/DE69932032T2/de
Application filed by Tanabe Seiyaku Co., Ltd. filed Critical Tanabe Seiyaku Co., Ltd.
Priority to BRPI9907040-5A priority patent/BR9907040B1/pt
Publication of WO1999036393A1 publication Critical patent/WO1999036393A1/fr
Priority to US09/619,712 priority patent/US6521666B1/en
Priority to IL137385A priority patent/IL137385A/en
Priority to HK01100247A priority patent/HK1029979A1/xx
Priority to US10/286,777 priority patent/US6855843B2/en
Priority to CY20061100959T priority patent/CY1105433T1/el

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/14—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
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    • C07C251/40—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to pharmaceutical compositions comprising molecules that are inhibitors of ⁇ 4 mediated (including ⁇ 4 ⁇ 7 ) adhesion and which could be useful in treating conditions such as asthma, diabetes, rheumatoid arthritis, inflammatory bowel disease and other diseases involving leukocyte infiltration of the gastrointestinal tract or other epithelial lined tissues; such as, skin, urinary tract, respiratory airway and joint synovium.
  • ⁇ 4 mediated including ⁇ 4 ⁇ 7
  • the inhibitors of the present invention could also be useful in treating conditions involving leukocyte infiltration of other tissues including lung, blood vessels, heart and nervous system as well as transplanted organs such as kidney, liver, pancreas and heart.
  • the adhesion of leukocyte to endothelial cells or extracellular matrix proteins is a fundamental process for immunity and inflammation and involves multiple adhesive interactions.
  • the earliest events in this process include leukocyte rolling followed by changes in integrin avidity, which leads to subsequent firm adhesion (for reviews see Butcher, Cell 67:1033-1036 (1991); Harlan, Blood 3 : 513-525 (1985); Hemler, Annu . Rev. Immunol . 8:365-400 (1990); Osborn, Cell 62:3-6 (1990); Shimizu et al., Immunol . Rev. 114:109-143 (1990); Springer, Na ture 346:425-434 (1990); Springer, Cell 76:301-314 (1994)).
  • the leukocytes In response to chemotactic factors, the leukocytes must migrate through two adjacent endothelial cells and into tissues that are composed, in part, of the extracellular matrix protein fibronectin (FN) (see ayner et al . , J. Cell Biol . 105:1873-1884 (1987)) and collagen (CN) (see Bornstem et al., Ann . Rev. Biochem . 49:957-1003 (1980) and Miller, Chemistry of the collagens and their distribution. In Connective Tissue Biochemistry. K.A. Piez and A.H. Reddi, editors. Elsevier, Amsterdam. 41-78.
  • FN extracellular matrix protein fibronectin
  • CN collagen
  • Important recognition molecules that participate in these reactions belong to the lntegnn gene superfamily (for reviews see Hemler, Annu . Rev. Immunol . 8:365-400 (1990); Hynes, Cell 48:549-554 (1987); Shimizu et al . , Immunol . Rev. 114:109- 143 (1990); and Springer, Na ture 346:425-434 (1990)).
  • Integ ⁇ ns are composed of non-covalently associated subunits, referred to as the alpha ( ⁇ ) and beta ( ⁇ ) subunits (for reviews see Hemler, Annu . Rev. Immunol . 8:365-400 (1990); Hynes, Cell 48:549-554 (1987); Shimizu et al., Immunol . Rev. 114:109-143 (1990); and Springer, Na ture 346:425-434 (1990)). To date, 8 mtegrin ⁇ subunits have been identified which can associate with 16 distinct ⁇ subunits to form 22 distinct integ ⁇ ns .
  • the ⁇ 7 mtegrin subunit first cloned by Erie et al., (Erie et al., J. Biol . Chem . 266:11009-11016 (1991)) is expressed only on leukocytes and is known to associate with two distinct ⁇ subunits, ⁇ 4 (Ruegg et al . , J. Cell Biol . 117:179-189 (1992)) and ⁇ E (Cerf-Bensussan et al., Eur . J. Immunol . 22:273-277 (1992) and Kilshaw et al . , Eur . J. Immunol . 21:2591-2597 (1991)).
  • the ⁇ E ⁇ 7 heterodimer has E-cadhenn as its sole ligand.
  • the ⁇ 4 ⁇ 7 complex has three known ligands (VCAM, CS-1, MAdCAM) .
  • VCAM VCAM
  • CS-1 CS-1
  • MAdCAM Mucosal Addressing Cell Adhesion Molecule
  • MAdCAM is highly expressed on Peyer's patch high endothelial venules, m mesenteric lymph nodes, and on gut lamina prop ⁇ a and mammary gland venules (Berg et al., Immunol . Rev. 105:5
  • Integ ⁇ n ⁇ 4 ⁇ 7 and MAdCAM have been shown to be important m regulating lymphocyte trafficking to normal intestine (Holzmann et al., Cell 56:37 (1989)).
  • the second ligand for ⁇ 4 ⁇ 7 is connecting segment 1
  • the cell-binding site within this alternatively spliced region is composed of 25 amino acids where the carboxy terminal ammo acid residues, EILDVPST, form the recognition motif (see Komoriya et al . , J. Biol . Chem . 266:15075-15079 (1991) and Wayner et al., J. Cell Biol . 116:489-497 (1992)).
  • VCAM-1 vascular cell adhesion molecule 1
  • cytokine mducible protein expressed on endothelial cells
  • VCAM and CS-1 are two ligands which are shared by ⁇ 4 ⁇ 7 and ⁇ 4 ⁇ l. It remains to be unequivocally shown whether MAdCAM, VCAM and CS-1 bind to the same site on ⁇ 4 ⁇ 7. Using a panel of monoclonal antibodies, Andrew et al . , showed that ⁇ 4 ⁇ 7 interaction with its three ligands involve distinct but overlapping epitopes (Andrew et al., J. Immunol 153:3847- 3861 (1994) ) . Utility of the Invention
  • Monoclonal antibody to ⁇ 4 inhibits insulitis and delays the onset of diabetes in the non-obese diabetic mouse (see Baron et al . , J. Clin . Invest . 93:1700-1708 (1994); Burkly et al . , Diabetes 43:529-534 (1994); and Yang et al . , Proc . Na tl . Acad. Sci . USA 90:10494-10498 (1993)).
  • Other diseases where 4 has been implicated include rheumatoid arthritis (see Laffon et al., J. Clin . Invest . 88:546-552 (1991) and Morales-Ducret et al., J. Immunol .
  • CD4 + , CD8 + T-cells, B- cells, NK cells, and eosinophils from human peripheral blood were shown to express high levels of ⁇ 4 ⁇ 7 (see Picarella et al . , J. Immunol . 158:2099-2106 (1997)).
  • N-termmal domain (domain 1) of MAdCAM has homology to the N-termmal mtegrm recognition domains in both VCAM and ICAM (see Briskm et al . , Na ture 363:461-464 (1993)).
  • the binding motif was identified in the first domain as three linear am o acid residues within a C-D loop (see Viney et al., J. Immunol . 157:2488-2497 (1996)).
  • Mutations of L40, D41 and T42 resulted in a complete loss of binding activity to ⁇ 4 ⁇ 7, suggesting that LDT on MAdCAM is involved in binding loop (see Viney et al., J. Immunol.
  • BOP-C1 Bis (2-oxo-3-oxazol ⁇ dmyl) phosphmic chloride
  • BOP reagent Benzotr ⁇ azol-1-yloxy-tr ⁇ s (dimethylammo) - phosphonium hexaf luorophosphate
  • DCC 1 , 3-D ⁇ cyclohexylcarbod ⁇ m ⁇ de
  • DIAD Diisopropyl azodicarboxylate
  • lower preceding a group such as alkyl, alkoxy, alkylene or alkane are meant to encompass 1 to 6 carbon atoms either in a straight chain or in a branched chain and the use of "lower” preceding alkanoyl, alkenyl, or alkenylene are meant to encompass 2 to 7 carbon atoms either in a straight chain or in a branched chain.
  • lower preceding cycloalkyl or cycloalkoxy are meant to encompass 3 to 7 carbon atoms.
  • phrases such as "morpholino-lower alkyl", “hydroxy-lower alkoxy” and the like are meant to refer to groups wherein the functional group preceding the hyphen is a substituent of the functional group that follows the hyphen.
  • hydroxy-lower alkoxy would refer to a lower alkoxy group containing at least one hydroxy substituent .
  • phrases such as "a lower alkyl group substituted by a halogen atom", "phenyl group substituted by a lower alkoxy group” and the like are meant to refer to functional groups containing at least one substituent.
  • a lower alkyl group substituted by a halogen atom would refer to a lower alkyl group containing at least one halogen atom
  • phenyl group substituted by a lower alkoxy group would refer to at least one lower alkoxy group.
  • This type of phraseology is meant to be interpreted by one of skill in the art, therefore, any deviations and combinations of this type of nomenclature is also within the abilities of those skilled in the art to interpret. Accordingly, this type of nomenclature is not to be applied to combinations that would not result in a realistic type of molecule or substituent.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising therapeutically effective amount of a compound of the formula [I] :
  • Ring A is an aromatic hydrocarbon ring or a heterocyclic ring
  • Q is a bond, a carbonyl group, a lower alkylene group which may be substituted by a hydroxyl group or phenyl group, a lower alkenylene group, or a -0- (lower alkylene) - group; n is an integer of 0, 1 or 2;
  • Z is oxygen atom or sulfur atom
  • R 1 , R 2 and R 3 are the same or different and are selected from the group consisting of: a) hydrogen atom, b) a halogen atom, c) a substituted or unsubstituted lower alkyl group, d) a substituted or unsubstituted lower alkoxy group, e) a nitro group, f) a substituted or unsubstituted am o group, g) a carboxyl group or an amide or an ester thereof, h) a cyano group, l) a lower alkylthio group, j ) a lower alkanesulfonyl group, k) a substituted or unsubstituted sulfamoyl group,
  • R 1 , R 2 and R 3 may combine each other at the terminal thereof to form a lower alkylenedioxy group
  • R 4 is tetrazolyl group, a carboxyl group, or an amide or an ester thereof;
  • R 5 is a group selected from the group consisting of: a) a hydrogen atom, b) a nitro group, c) a substituted or unsubstituted ammo group, d) a nydroxyl group, e) a lower alkanoyl group, f) a substituted or unsubstituted lower alkyl group, g) a lower alkoxy group, h) a halogen atom, and
  • R 6 is a group selected from the group consisting of : a) a substituted or unsubstituted phenyl group, and b) a substituted or unsubstituted heteroaryl group; or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a method for treating or preventing conditions caused by ⁇ 4 (including 4 ⁇ and o. 4 ⁇ ) mediated cell adhesion which comprises administering a compound of the formula [I] .
  • the present invention also relates to a novel compound, which is a compound of the formula [I] with the proviso that when Ring A is a benzene ring, it is not substituted with methyl group in the 3- and the 5-pos ⁇ t ⁇ ons or in the 2- and the 4-pos ⁇ t ⁇ ons; or a pharmaceutically acceptable salt thereof.
  • novel compound of the present invention may exist in the form of optical isomers based on asymmetric carbon atoms thereof, and the present invention also includes these optical isomers and mixtures thereof.
  • the steric configuration of the compound need not be fixed.
  • the compound of the present invention may be a compound with a sole configuration or a mixture thereof with several different configurations.
  • aromatic hydrocarbon ring may be a mono-, bi- or t ⁇ -cyclic aromatic hydrocarbon ring such as a benzene ring, a naphthalene ring, an anthracene ring, a fluorene ring.
  • heterocyclic ring may be a heteroatom-contammg mono-, bi- or tri-cyclic ring.
  • heterocyclic ring may be py ⁇ dme ring, pyrimidme ring, pyridazme ring, pyrazme ring, qumolme ring, lsoqumol e ring, qumazolme ring, phthalaz e ring, lmidazole ring, isoxazole ring, pyrazole ring, oxazole ring, thiazole ring, mdole ring, benzazole ring, benzothiazole ring, benzimidazole ring, benzofuran ring, furan ring, thiophene ring, pyrrole ring, oxadiazole ring, thiadiazole ring, triazole ring, tetrazole ring, pyrrol
  • aryl group may be a mono-, bi- or tri-cyclic aromatic group.
  • Examples of “aryl group” may be a phenyl group, a naphthyl group, an anthryl group and a fluorenyl ring.
  • heterocyclic group may be a mono-, bi- or tri-cyclic ring containing a heteroatom such as nitrogen atom, oxygen atom, and sulfur atom.
  • heterocyclic group may be pyridyl group, pyrimidmyl group, py ⁇ dazmyl group, pyraz yl group, qumolyl group, isoquinolyl group, quinazolinyl group, phthalazmyl group, lmidazolyl group, isoxazolyl group, pyrazolyl group, oxazolyl group, thiazolyl group, indolyl group, benzazolyl group, benzothiazolyl group, benzimidazolyl group, benzofuranyl group, furyl group, thienyl group, pyrrolyl group, oxadiazolyl group, thiadiazolyl group, t ⁇ azolyl group, tetrazoly
  • heteroaryl group may be a mono-, bi- or tri-cyclic aromatic group containing a heteroatom such as nitrogen atom, oxygen atom, and sulfur atom.
  • heteroaryl group may be a "heterocyclic ring” other than pyrrolidmyl group, pyrrolmyl group, piperidmyl group, piperazmyl group, morpholmyl group, and tetrahydropyranyl group.
  • Preferable examples of the "heteroaryl group” may be pyridyl group, thienyl group, benzofuranyl group, py ⁇ midyl group, and isoxazolyl group.
  • Ring P is an aromatic hydrocarbon ring or a heterocyclic ring
  • Q is a bond, a carbonyl group, a lower alkylene group which may be substituted by a hydroxyl group or phenyl group, a lower alkenylene group, or a -0- (lower alkylene) - group; n is an integer of 0, 1 or 2;
  • Z is oxygen atom or sulfur atom
  • R 1 , R 2 and R 3 are the same or different and are selected from the group consisting of: a) hydrogen atom, b) a halogen atom, c) a substituted or unsubstituted lower alkyl group, d) a substituted or unsubstituted lower alkoxy group, e) a nitro group, f) a substituted or unsubstituted ammo group, g) a carboxyl group or an amide or an ester thereof, h) a cyano group,
  • R 1 , R 2 and R 3 may combine each other at the terminal thereof to form a lower alkylenedioxy group
  • R 4 is tetrazolyl group, a carboxyl group, or an amide or an ester thereof;
  • R 5 is a group selected from the group consisting of: a) a hydrogen atom, b) a nitro group, c) a substituted or unsubstituted ammo group, d) a hydroxyl group, e) a lower alkanoyl group, f) a substituted or unsubstituted lower alkyl group, g) a lower alkoxy group, h) a halogen atom, and j ) 2-oxopyrrol ⁇ d ⁇ nyl group;
  • R is a group selected from the group consisting of : a) a substituted or unsubstituted phenyl group, b) a substituted or unsubstituted heteroaryl group; with the proviso that when Ring A is a benzene ring, the ring is not substituted with methyl group in the 3- and the 5-pos ⁇ t ⁇ ons or in the 2- and the 4-pos ⁇ t ⁇ ons; or a pharmaceutically acceptable salt thereof.
  • a preferred configuration of the active ingredient of the present invention is represented by the formula [I-A]:
  • a preferred embodiment of the present invention is the compound [I] with the additional proviso that when Ring A is a benzene ring, the ring is substituted in at least one of 2- and 6-pos ⁇ t ⁇ ons.
  • R 1 , R 2 and R 3 are selected from the group consisting of: hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkoxy group, a nitro group, a substituted or unsubstituted amino group, a carboxyl group or an amide or an ester thereof, a cyano group, a lower alkylthio group, a lower alkanesulfonyl group, a substituted or unsubstituted sulfamoyi group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, and m) hydroxyl group, or two of R 1 , R 2 and R 3 may combine with each other at the terminal thereof to form a lower alkylenedioxy group.
  • a more preferred configuration of the active ingredient of the present invention is represented by the formula [I-B] : wherein symbols are the same as defined above.
  • R 1 is hydrogen atom, a halogen atom, carboxyl group, carbamoyl group, nitro group, a substituted or unsubstituted am o group, a substituted or unsubstituted heterocyclic ring;
  • R 2 is hydrogen atom, a lower alkyl group or a halogen atom
  • R 3 is hydrogen atom, a lower alkyl group or a halogen atom
  • R 6 is a phenyl group which may be substituted at 2-, 4-, and/or 6-pos ⁇ t ⁇ on of the phenyl group by a group selected from the group consisting of:
  • R 6 is a phenyl group which may be substituted by a group selected from the group consisting of:
  • a lower alkyl group which may be substituted by a group selected from a substituted or unsubstituted ammo group, a substituted or unsubstituted piperidmyl group, a substituted or unsubstituted morpholino group, a substituted or unsubstituted piperazmyl group, a substituted or unsubstituted pyrrolidmyl group, and a substituted or unsubstituted lmidazolidmyl group.
  • a substituted or unsubstituted ammo group a substituted or unsubstituted piperidmyl group, a substituted or unsubstituted morpholino group, a substituted or unsubstituted piperazmyl group, a substituted or unsubstituted pyrrolidmyl group, and a substituted or unsubstituted lmidazolidmyl group.
  • Ring A is a benzene ring, a pyridine ring, a pyrazine ring, a furan ring, an isoxazole ring, a benzofuran ring, a thiophene ring, a pyrrole ring, or an indole ring;
  • R , R and R are selected from the group consisting of: a) hydrogen atom, b) a halogen atom, c) a lower alkyl group which may be substituted by a halogen atom or a (halogenobenzoyl ) amino group, d) a lower alkoxy group which may be substituted by a halogen atom, e) a nitro group, f) an amino group which may be substituted by 1-2 groups selected from the group consisting of 1) a lower alkyl group, 2) a lower alkanoyl group, 3) a halogenobenzoyl group, 4) a lower alkoxycarbonyl group, 5) a lower alkanesulfonyl group which may be substituted by a halogen atom, 6) a benzenesulfonyl group which may be substituted by a lower alkyl group, a trihalogeno-lower alkyl group, a halogen
  • a lower alkanesulf onyl group m) a sulfamoyl group, n) a phenyl group, o) a pyrrolidmyl group which may be substituted by oxo group, p) a pyrrolyl group which may be substituted by a group selected from the group consisting of 1) a lower alkanoyl group which may be substituted by a halogen atom, 2) a halogen atom, 3) formyl group, and 4) a lower alkyl group which may be substituted by hydroxy group, q) a thienyl group, r) an isoxazolyl group which may be substituted by a lower alkyl group, s) a thiazolyl group, t) a pyrazolyl group, u) a pyrazinyl group, v) a pyridyl group, and w) hydroxyl group;
  • R is selected from the group consisting of: a) carboxyl group, b) a lower alkoxycarbonyl group which may be substituted by 1) pyridyl group or 2) an ammo group which may be substituted by a lower alkyl group, c) a lower cycloalkoxy carbonyl group, d) a caroamoyl group which may be substituted by a hydroxy group or a lower alkanesulfonyl group, and e) a tetrazolyl group;
  • R is selected from the group consisting of: a) a hydrogen atom, b) a nitro group, c) an ammo group which may be substituted by a lower alkanoyl group, a lower alkoxycarbonyl group or a lower alkanesulfonyl group, d) a hydroxyl group, e) a lower alkanoyl group, f) a lower alkyl group which may be substituted by 1) hydroxyl group, or 2) an imino group which is substituted by hydroxyl group or a lower alkoxy group, g) a lower alkoxy group, h) a halogen atom, l) 2-oxopyrrol ⁇ dmyl group;
  • R is the group selected from the group consisting of
  • a lower alkoxy group which may be substituted by a group selected from the group consisting of l) a carboxyl group or an amide or an ester thereof, n) hydroxyl group, in) a cyano group, iv) a halogen atom, v) an ammo group which may be substituted by a lower alkyl group, vi) a pyridyl group, vn) a thiazolyl group which may be substituted by a lower alkyl qroup, vm) an isoxazolyl group which may be substituted by a lower alkyl group, IX) a piperidyl group which may be substituted by a lower alkyl group, x) a pyrrolidmyl group which may be substituted by a lower alkyl group, xi) a phenyl group which may be substituted by a halogen atom, xu) a furyl group, xm) a group selected
  • a lower alkyl group which may be substituted by a group selected from the group consisting of I) a halogen atom, ii) hydroxyl group, m) carboxyl group or an amide or an ester thereof, iv) a lower alkoxy group, v) an ammo group which may be substituted by 1-2 groups selected from the group consisting of a lower alkyl group, a hydroxy-lower alkyl group, a (lower alkylamino) -lower alkyl group, phenyl-lower alkyl group, a phenyl group, and a pyridyl group, vi) a piperidinyl group which may be substituted by a lower alkylenedioxy group, an oxo group or a hydroxy group, vii) a morpholino group which may be substituted by a lower alkyl group, viii) thiomorpholino group which may be oxidized, ix) piperaz
  • a carbamoyl group which may be substituted by a lower alkyl group, a hydroxy-lower alkyl group, a morpholino-lower alkyl group, a phenyl-lower alkyl group or a lower alkanesulfonyl group,
  • a sulfamoyl group which may be substituted by a group consisting of i) a lower alkyl group, ii) a benzoyl group, iii) a lower alkoxycarbonyl group, and iv) a lower alkanoyl group, 12) a lower alkenyloxy group,
  • a lower alkanoyl group d) a benzofuranyl group; e) a pyrimidmyl group which may be substituted by a lower alkoxy group; f) a isoxazolyl group which may be substituted by a lower alkyl group; and g) a pyrrolyl group which may be substituted by a lower alkoxycarbonyl group.
  • Ring A is a benzene ring
  • R is selected from the group consisting of: a) hydrogen atom, b) a halogen atom, c) a lower alkyl group, d) a lower alkoxy group, e) nitro group, f) an amino group which may be substituted by a group selected from the group consisting of 1) a lower alkyl group, 2) a lower alkanoyl group, 3) a lower alkoxycarbonyl group, 4) a lower alkanesulfonyl group which may be substituted by a halogen atom, 5) a benzenesulfonyl group which may be substituted by a lower alkyl group, a t ⁇ halogeno-lower alkyl group, a halogen atom or a lower alkoxy group, 6) thiophenesulfonyl group, 7) a carbamoyl group which may be substituted by a lower alkyl group or a lower alkyl-phenyl group,
  • a pyrrolyl group which may be substituted by a lower alkyl group, m) a thienyl group, n) an isoxazolyl group which may be substituted by a lower alkyl group, o) a thiazolyl group p) a pyrazolyl group, q) a pyrazmyl group, r) a pyridyl group, and s) hydroxyl group;
  • R is hydrogen atom, or a halogen atom
  • R is hydrogen atom, or a halogen atom
  • R is a) a carboxyl group, b) a lower alkoxycarbonyl group which may be substituted by a lower alkyl-amino group, or c) a carbamoyl group which may be substituted by a lower alkanesulfonyl group;
  • R is selected from the group consisting of: a) hydrogen atom, b) an amino group which may be substituted by a lower alkanoyl group, a lower alkoxycarbonyl group or a lower alkanesulfonyl group, c) a lower alkanoyl group, d) a lower alkyl group which may be substituted by 1) hydroxyl group, or 2) an imino group which is substituted by hydroxyl group or a lower alkoxy group, e) a lower alkoxy group, and f) a halogen atom;
  • R is a phenyl group which may have 1-5 substituents selected from the group consisting of: a) a halogen atom, b) a formyl group, c) a hydroxyl group, d) a lower alkoxy group which may be substituted by 1) a carboxyl group, 2) a hydroxyl group, 3) a cyano group, 4) a halogen atom, 5) an amino group which may be substituted by a lower alkyl group, 6) a pyridyl group, 7) a phenyl group, 8) a thienyl group, or 9) a lower alkoxy group, e) a lower alkyl group which may be substituted by 1) an amino group which may be substituted by a lower alkyl group, a hydroxy-lower alkyl group, a lower alkylamino- lower alkyl group or a phenyl group, 2) a piperidinyl group which may be substituted by
  • R is 1) hydrogen atom, 2) a halogen atom, 3) a lower alkanoylamino group, 4) a lower alkoxycarbonylamino group, 5) a lower alkanesulfonylamino group which may be substituted by a halogen atom, 6) a benzenesulfonylamino group which may be substituted by a lower alkyl group, a trihalogeno-lower alkyl group, a halogen atom or a lower alkoxy group, 7) thiophenesulfonylamino group, 8) an ureido group which may be substituted by a lower alkyl group or a lower alkyl-phenyl group, 9) a lower alkyl-thioureido group, or 10) a lower alkylsulfamoylam o group, R 2 is a halogen atom, R 3 is hydrogen atom or
  • R 1 is hydrogen atom
  • R 3 is a halogen atom
  • R 6 is 2- (lower alkoxy) phenyl group, 2,6-d ⁇ (lower alkoxy) phenyl group, 2,6-d ⁇ (lower alkoxy) -4- [ [N, N-di ( lower alkyl) ammo] lower alkyl]phenyl group, 2 , 6-d ⁇ ( lower alkoxy) - 4-[(4-lower alkyl-1-p ⁇ perazmyl ) lower alkyl]phenyl group, 2,6-d ⁇ (lower alkoxy) -4- [ 1-p ⁇ per ⁇ dmyl-lower alkyl]phenyl group, 2,6-d ⁇ (lower alkoxy) -4- [N, N-di (lower alkyl) - carbamoyl] phenyl group or 2,6-d ⁇ (lower alkoxy) -4- [ (morpholino) lower alkyl
  • a lower alkoxy group is methoxy group.
  • Preferred compounds as the active ingredient of the present invention may be selected from the group consisting of:
  • the active ingredient of the present invention may be used in the form of an ester or amide thereof.
  • ester there may be mentioned a) a lower alkyl ester which may be substituted by 1) pyridyl group, 2) an amino group which may be substituted by a lower alkyl group, 3) a lower alkanoyloxy group, 4) an aryl group; b) a lower alkenyl ester; c) a lower alkynyl ester; d) a lower cycloalkyl ester; e) an aryl ester.
  • an amide (-CONH 2 ) which may be substituted by 1) a lower alkyl group, a lower cycloalkyl group, aryl group, aryl-lower alkyl group, hydroxy group or a lower alkanesulfonyl group;
  • An ester of the formula [I] includes, for example, an ester which can be converted to the corresponding carboxylic acid in a body, for example, a lower alkyl ester (e.g., methyl ester), a lower alkanoyloxy-lower alkyl ester (e.g., acetoxymethyl ester) and the like.
  • An amide of the formula [I] includes, for example, an N-unsubstituted amide, an N-monosubstituted amide (e.g., an N-lower alkyl amide), an N, -disubstituted amide (e.g., an N,N- (lower alkyl) (lower alkyl) amide) and the like.
  • a pharmaceutically acceptable salt of the formula [I] includes, for example, a salt with an inorganic acid (e.g., hydrochloride, sulfate), a salt with an organic acid (e.g., p-toluenesulfonate, maleate), a salt with an inorganic base (e.g., a salt with an alkali metal such as a sodium salt or a potassium salt) or a salt with an amine (e.g., an ammonium salt) .
  • an inorganic acid e.g., hydrochloride, sulfate
  • an organic acid e.g., p-toluenesulfonate, maleate
  • a salt with an inorganic base e.g., a salt with an alkali metal such as a sodium salt or a potassium salt
  • a salt with an amine e.g., an ammonium salt
  • the active ingredient of the present invention may be used either in a free form or in the form of pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts include acid-addition salts with inorganic acid or organic acid (e.g., hydrochloride, sulfate, nitrate, hydrobromide, methanesulfonate, p-toluenesulfonate, acetate), salt with inorganic base, organic base or ammo acid (e.g., triethylamme salt, a salt with lysme, an alkali metal salt, an alkali earth metal, salt and the like) .
  • the active ingredient may be formulated into a pharmaceutical composition comprising a therapeutically effective amount of the compound as defined above and a pharmaceutically acceptable carrier or diluent.
  • the composition can be used for treating or preventing 0( 4 (including adhesion mediated conditions a mammal such as a human, especially used for treatment or prevention of ⁇ 7 adhesion mediated conditions.
  • This method may comprise administering to a mammal or a human patient an effective amount of the compound or composition as explained above .
  • This method can be used to treat or prevent such inflammatory conditions as rheumatoid arthritis, asthma, psoriasis, eczema, contact dermatitis and other skin inflammatory diseases, diabetes, multiple sclerosis, systemic lupus erythematosus (SLE), inflammatory bowel disease including ulcerative colitis and Crohn ' s disease, and other diseases involving leukocyte infiltration of the gastrointestinal tract, or other epithelial lined tissues, such as skin, urinary tract, respiratory airway, and joint synovium.
  • the method can be preferably used for treatment or prevention of inflammatory bowel disease including ulcerative colitis and Crohn ' s disease.
  • the present invention also relates to a method for inhibiting the interaction of a cell bearing a ligand of MAdCAM-1, including ⁇ 4 ⁇ 7 mtegrms, with MAdCAM-1 or a portion thereof (e.g., the extracellular domain), comprising contacting the cell with an active ingredient of the present invention.
  • the present invention relates to a method of inhibiting the MAdCAM- mediated interaction of a first cell bearing an 4 ⁇ 7 mtegrin with MAdCAM, for example with a second cell bearing MAdCAM, comprising contacting the first cell with an active ingredient of the present invention.
  • the invention relates to a method of treating an individual suffering from a disease associated with leukocyte recruitment to tissues (e.g., endothelium) expressing the molecular MAdCAM-1.
  • Another embodiment of the present invention is a method of treating an individual suffering from a disease associated with leukocyte infiltration of tissues expressing the molecule MAdCAM-1.
  • the cell bearing the ligand for MAdCAM-1 is contacted with an effective amount of an (i.e., one or more) inhibitor as represented by Structural Formula [I] .
  • an inhibitor is a compound which inhibits (reduces or prevents) the binding of MAdCAM-1 to a ligand, including ⁇ 4 ⁇ 7 mtegrm, and/or which inhibits the triggering of a cellular response mediated by the ligand.
  • An effective amount can be an inhibitory amount (such an amount sufficient to achieve inhibition of adhesion of a cell bearing a MAdCAM-1 ligand to MAdCAM-1) .
  • Ligands for MAdCAM-1 include ⁇ 4 ⁇ 7 mtegrms, such as human ⁇ 4 ⁇ 7 mtegrm, and its homologs from other species such as mice (also referred to as ⁇ 4 ⁇ p or LPAM-1 in mice) .
  • the adhesion of a cell which naturally expresses a ligand for MAdCAM-1 can be inhibited m vi tro and/or m vivo according to the present method.
  • a ligand for MAdCAM-1 such as a leukocyte (e.g., B lymphocyte, T lymphocyte) or other cells which express a ligand for MAdCAM-1 (e.g., a recombinant cell)
  • a ligand for MAdCAM-1 such as a leukocyte (e.g., B lymphocyte, T lymphocyte) or other cells which express a ligand for MAdCAM-1 (e.g., a recombinant cell)
  • a ligand for MAdCAM-1 e.g., a recombinant cell
  • the present invention relates to a method of treating an individual (e.g., a mammal, such as a human or other primate) suffering from a disease associated with leukocyte (e.g., lymphocyte, monocyte) infiltration of tissues (including recruitment and/or accumulation of leukocytes in tissues) which express the molecule MAdCAM-1.
  • the method comprises administering to the individual a therapeutically effective amount of an inhibitor (i.e., one or more inhibitors) of Structural Formula [I] .
  • inflammatory diseases including diseases which are associated with leukocyte infiltration of the gastrointestinal tract (including gut-associated endothelium) , other mucosal tissues, or tissues expressing the molecular MAdCAM-1 (e.g., gut-associated tissues, such as venules of the lamina intestinal of the small and large intestine; and mammary gland (e.g., lactating mammary gland)), can be treated according to the present method.
  • an individual suffering from a disease associated with leukocyte infiltration of tissues as a result of binding of leukocytes to cells (e.g., endothelial cells) expressing the molecule MAdCAM-1 can be treated according to the present invention.
  • IBD inflammatory bowel disease
  • Crohn' s disease and pouchitis resulting after proctocolectomy and lleoanal anastomosis after IBD inflammatory bowel disease
  • other gastrointestinal diseases associated with leukocyte infiltration such as Celiac disease, nontropical Sprue, enteropathy associated with seronegative arthropathies , lymphocytic and graft versus host diseases.
  • Pancreatitis and insulin-dependent diabetes mellitus are other diseases which can be treated using the present method. It has been reported that MAdCAM-1 is expressed by some vessels in the exocrme pancreas from NOD (nonobese diabetic) mice, as well as from BALB/c and SJL mice. Expression of MAdCAM-1 was reportedly induced on endothelium m inflamed islets of the pancreas of the NOD mouse, and MAdCAM-1 was the predominant address in expressed by NOD islet endothelium at early stages of msulitis (Hannmen, A. et al . , J. Clin. Invest., 92: 2509- 2515 (1993)).
  • lymphocytes expressing ⁇ 4 ⁇ 7 within islets were observed, and MAdCAM-1 was implicated in the binding of lymphoma cells via ⁇ 4 ⁇ 7 to vessels from inflamed islets (Hannmen, A., et al., J. Clin. Invest., 92: 2509-2515 (1993)).
  • inflammatory diseases associated with mucosal tissues which can be treated according to the present method include mastitis (mammary gland) , cholecystitis, cholangitis or pericholangitis (bile duct and surrounding tissue of the liver), chronic bronchitis, chronic sinusitis, asthma, and graft versus host disease (e.g., in the gastrointestinal tract).
  • Chronic inflammatory diseases of the lung which result in interstitial fibrosis, such as hypersensitivity pneumonitis, collagen disease (in SLE and RA) , sarcoidosis, and other ldiopathic conditions can be amenable to treatment .
  • VCAM-1 Vascular cell adhesion molecule-1
  • VLA-4 ⁇ 4 ⁇ l mtegrm
  • MAdCAM-1 is preferentially expressed in the gastrointestinal tract and mucosal tissues, binds the ⁇ 4 ⁇ 7 mtegrm found on lymphocytes, and participates in the homing of these cells to mucosal sites, such as Peyer' s patches in the intestinal wall (Hamann et al . , J. Immunol., 152:3282-3293 (1994)).
  • the active ingredients of the present invention have the potential for fewer side effects due to, for example, effects on other tissue types wnere adhesion is mediated by other receptors, such as ⁇ 4 ⁇ l mtegrm .
  • Undesired symptoms of the condition listed herein can alleviated using the present method.
  • the symptoms may be caused by inappropriate cell adhesion and/or cell activation to release promflammatory mediators mediated by ⁇ 4 ⁇ 7 mtegrms.
  • Such inappropriate cell adhesion or signal transduction would typically be expected to occur as a result of increased VCAM and/or MAdCAM expression on the surface of endothelial cells.
  • Increased VCAM, MAdCAM and/or CS-1 expression can be due to a normal inflammatory response or due to abnormal inflammatory states.
  • the present method can be used to assess the inhibitory effect of a compound of the present invention and of other potential antagonists useful in the method on the interaction of MAdCAM-1 with a ligand for MAdCAM-1 in
  • Suitable animal models of inflammation have been described.
  • NOD mice provide animal model of msulm-dependent diabetes mellitus.
  • CD45 RB Hl SCID model provide a model in mice with similarity to both Crohn' s disease and ulcerative colitis (Pow ⁇ e, F. et al . , Immunity, 1: 553-562 (1994)).
  • Captive cotton-top tamarms a New World nonhuman primate species, develop spontaneous, often chronic, colitis that clinically and histolgocially resembles ulcerative colitis in humans (Madara, J.L.
  • an inhibitor can be administered to an individual (e.g., a human) alone or m conjunction with another agent, such as an additional pharmacologically active agent (e.g., sulfasalazme, an antunflammatory compound, or a steroidal or other nonsteroidal antunflammatory compound) .
  • an additional pharmacologically active agent e.g., sulfasalazme, an antunflammatory compound, or a steroidal or other nonsteroidal antunflammatory compound
  • a compound can be administered before, along with or subsequent to administration of the additional agent, n amounts sufficient to reduce or prevent MAdCAM-mediated binding to a ligand for MAdCAM-1, such as human ⁇ 4 ⁇ 7 .
  • An effective amount of the active ingredient can be administered by an appropriate route in a single dose or multiple doses.
  • An effective amount is a therapeutically effective amount sufficient to achieve the desired therapeutic and/or prophylactic effect (such as an amount sufficient to reduce or prevent MAdCAM-mediated binding to a MAdCAM ligand, thereby inhibiting leukocyte adhesion and infiltration and associated cellular responses.
  • Suitable dosages of active ingredient of the present invention for use in therapy, diagnosis or prophylaxis can be determined by methods known in the art and can be dependent, for example, upon the individual's age, sensitivity, tolerance and overall well-being.
  • the active ingredient of the present invention or pharmaceutically acceptable salts thereof may be administered either orally or parenterally, and it may be used as a suitable pharmaceutical preparation, for example, a tablet, a granule, a capsule, a powder, an injection, and an inhalation by a conventional process.
  • the dose of the active ingredient of the present invention or a pharmaceutically acceptable salt thereof varies depending on an administration method, age, body weight, and state of a patient, but, in general, the daily dose is preferably about 0.1 to 100 mg/kg/day, particularly preferably 1 to 100 mg/kg/day.
  • the active ingredient of formula [I] can be formulated into pharmaceutical compositions.
  • the particular disease in question, its severity, as well as the age, sex, weight, and condition of the subject to be treated, must be taken into consideration and this perusal is to be determined by the skill of the attendant physician.
  • a suitable daily dose of a compound of Formula [I], or a pharmaceutically acceptable salt thereof, for a mammalian subject suffering from, or likely to suffer from, any condition as described herein before is 0.1 mg to 100 mg of the compound of formula [I], per kilogram body weight of the (systemic) mammalian subject.
  • the dose may be in the range of 0.5 to 100 mg of the compound per kilogram body weight, the most preferred dosage being 0.5 to 50 mg/kg of mammal body weight administered two to three times daily.
  • a suitable dose may be in the range of 0.1 ⁇ g to 100 ⁇ g of the compound per kilogram, typically about 0.1 ⁇ g/kg.
  • a suitable dose of a compound of Formula [I], or a physiologically acceptable salt thereof may be as specified in the preceding paragraph, but preferably is from 1 mg to 50 mg of the compound per kilogram, the most preferred dosage being from 5 mg to 25 mg/kg of mammal body weight, for example, from 1 to 10 mg/kg.
  • a unit dosage of an orally administrable composition encompassed by the present invention contains less than about 1.0 g of a formula [I] compound.
  • the compounds and compositions of the present invention can be administered to patients suffering from a condition listed herein in an amount which is effective to fully or partially alleviate undesired symptoms of the condition.
  • the symptoms may be caused by inappropriate cell adhesion or cell activation to release proinflammatory mediators mediated by ⁇ 4 ⁇ 7 integrins.
  • Such inappropriate cell adhesion or signal transduction would typically be expected to occur as a result of increased VCAM-1 and/or MAdCAM expression on the surface of endothelial cells.
  • Increased VCAM-1, MAdCAM and/or CS-1 expression can be due to a normal inflammation response or due to abnormal inflammatory states.
  • an effective dose of a compound of the invention may reduce the increased cell adhesion due to increased VCAM-1 and/or MAdCAM expression by endothelial cells . Reducing the adhesion observed in the disease state by 50% can be considered an effective reduction in adhesion. More preferably, a reduction in ex vivo adhesion by 90%, is achieved. Most preferably, adhesion mediated by VCAM-1, MAdCAM and/or CS-1 interaction is abolished by an effective dose. Clinically, in some instances, effect of the compound can be observed as a decrease in white cell infiltration into tissues or a site of injury. To achieve a therapeutic effectiveness, then, the compounds or compositions of the present invention are administered to provide a dose effective to reduce or eliminate inappropriate cell adhesion or inappropriate cell activation to alleviate undesired symptoms .
  • an active ingredient While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation comprising a compound of Formula [I] and a pharmaceutically acceptable carrier thereof. Such formulations constitute a further feature of the present invention .
  • the formulations, both for human and veterinary medical use, of the present invention comprise an active ingredient of Formula [I], in association with a pharmaceutically acceptable carrier thereof and optionally other therapeutic ingredient (s) , which are generally known to be effective in treating the disease or condition encountered.
  • the carrier (s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
  • the formulations include those in a form suitable for oral, pulmonary, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), tra- articular, topical, nasal inhalation (e.g., with an aerosol) or buccal administration.
  • parenteral including subcutaneous, intramuscular, and intravenous
  • tra- articular topical
  • nasal inhalation e.g., with an aerosol
  • buccal administration Such formulation are understood to include long-acting formulations known in the art .
  • Oral and parenteral administration are preferred modes of administration .
  • the formulations may conveniently be presented m unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods may include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired form.
  • Formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient in the form of a powder or granules; in the form of a solution or suspension in an aqueous liquid.
  • Formulations for other uses could involve a nonaqueous liquid; in the form of an oil-in-water emulsion or a water-m-oil emulsion; in the form of an aerosol; or in the form of a cream or ointment or impregnated into a transdermal patch for use in administering the active ingredient transdermally, to a patient in need thereof.
  • the active ingredient of the present inventive compositions may also be administered to a patient in need thereof in the form of a bolus, electuary, or paste.
  • novel compound [I] can be prepared by the following methods.
  • the compound of the formula [I] or a pharmaceutically acceptable salt thereof may be prepared by :
  • a salt of the compound [II] and/or [III] includes, for example, a salt with an inorganic acid (e.g., trifluoroacetate, hydrochloride, sulfate) , a salt with an inorganic base (e.g., an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a barium salt or calcium salt) .
  • an inorganic acid e.g., trifluoroacetate, hydrochloride, sulfate
  • an inorganic base e.g., an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a barium salt or calcium salt
  • the condensation reaction can be carried out by a conventional method for a usual amide bond synthesis .
  • the condensation reaction of the compound [II] or a salt thereof with the compound [III] or a salt thereof is carried out in the presence of a condensing reagent with or without a base in a suitable solvent or without a solvent.
  • the condensing reagent can be selected from any one which can be used for a conventional amide bond synthesis, for example, B0P-C1, BOP reagent, DCC, EDC or CDI .
  • the base can be selected from an organic base (e.g., DIEA, DMAP, DBU, Et 3 N) , an alkali metal hydride (e.g., NaH, LiH) , an alkali metal carbonate (e.g., Na 2 C0 3 , K 2 C0 3 ) , an alkali metal hydrogen carbonate (e.g., NaHC0 3 , KHCO3) , an alkali metal amide (e.g., NaNH 2 ) , an alkali metal alkoxide (e.g., NaOMe, KOMe) , a lower alkyl alkali metal salt (e.g., n-BuLi, t-BuLi), an alkali metal hydroxide (e.g., NaOH, KOH) , an alkaline earth metal hydroxide (e.g., Ba(OH) 2 ), and the like.
  • an organic base e.g., DIEA, DMAP, DBU, Et
  • the solvent can be selected from any one which does not disturb the condensation reaction, for example, CH2CI2, THF, DMF or a mixture thereof.
  • the reaction is carried out at a temperature of 0 °C to room temperature, preferably at room temperature.
  • an acid halide e.g., an acid chloride
  • a reactive ester e.g., an ester with p- mtrophenol
  • an anhydride thereof e.g., a mixed anhydride with other carboxylic acid (e.g., a mixed anhydride with acetic acid) , and the like
  • the base can be selected from an organic base (e.g., DIEA, DMAP, DBU, Et 3 N) , an alkali metal hydride (e.g., NaH, LiH) , an alkali metal carbonate (e.g., Na 2 C0 3 , K 2 C0 3 ) , an alkali metal hydrogen carbonate (e.g., NaHCOj, KHCO 3 ), an alkali metal amide (e.g., NaNH 2 ) , an alkali metal alkoxide (e.g., NaOMe, KOMe), a lower alkylalkali metal salt (e.g., n-BuLi, t-BuLi), an alkali metal hydroxide (e.g., NaOH, KOH), an alkaline earth metal hydroxide (e.g., Ba(OH) 2 ), and the like.
  • an organic base e.g., DIEA, DMAP, DBU, Et 3 N
  • the solvent can be selected from any one which does not disturb the condensation reaction, for example, CH 2 C1 2 , C 2 H 4 CI 2 , Et 2 0, THF, DMF, CH 3 CN, DMSO, benzene, toluene or a mixture thereof.
  • the reaction is carried out at a temperature of -30 °C to 100 °C .
  • the conversion of the ester group into a carboxyl group can be carried out by a conventional method, which is selected according to the type of the ester group to be removed, for example, hydrolysis using a base (e.g., LiOH, NaOH) or an acid (e.g., HC1), treatment with an acid (e.g., TFA) , catalytic reduction using a catalyst (e.g., palladium on activated carbon) and the like.
  • a base e.g., LiOH, NaOH
  • an acid e.g., HC1
  • treatment with an acid e.g., TFA
  • catalytic reduction using a catalyst e.g., palladium on activated carbon
  • the ester group can be selected from a conventional ester, for example, a lower alkyl ester, a lower alkenyl ester, a lower alkynyl ester, an aryl-lower alkyl ester (e.g., benzyl ester), an aryl ester (e.g., phenyl ester) and the like.
  • a conventional ester for example, a lower alkyl ester, a lower alkenyl ester, a lower alkynyl ester, an aryl-lower alkyl ester (e.g., benzyl ester), an aryl ester (e.g., phenyl ester) and the like.
  • the compound of the formula [I] can be prepared by:
  • Examples of the leaving group X 1 may be a halogen atom and a trifluoromethanesulfonyloxy group.
  • the coupling reaction can be carried out by a conventional aryl coupling method, e.g., Suzuki coupling method (for reference of Suzuki coupling method: (a) Suzuki et al., Synth . Commun . 1981, 11 , 513, (b) Suzuki, Pure and Appl . Chem . 1985, 57, 1749-1758, (c) Suzuki et al . , Chem . Rev. 1995, 95, 2457-2483, (d) Shieh et al . , J. Org . Chem . 1992, 57, 379-381), (e) Martin et al . , Acta Chemica Scandinavica , 1993, 47, 221-230.)
  • Suzuki coupling method for reference of Suzuki coupling method: (a) Suzuki et al., Synth . Commun . 1981, 11 , 513, (b) Suzuki, Pure and Appl . Chem . 1985, 57, 1749-1758, (c)
  • the coupling reaction can be carried out, for example, at a temperature of room temperature to 100 °C, preferably at a temperature of 80 °C to 100 °C, in the presence of tetrakis (triphenylphosphme) palladium and a base (e.g., an inorganic base such as K 2 C0 3 ) m an organic solvent.
  • a base e.g., an inorganic base such as K 2 C0 3
  • the organic solvent can be selected from any one which does not disturb the coupling reaction, for example, toluene, DME, DMF, H 2 0 or a mixture thereof.
  • the compound of the formula [I] can be also prepared by:
  • Examples of the leaving group X is a halogen atom and a trifluoromethanesulfonyloxy group.
  • the conversion of the compound [IV] to the organotin compound [VII] can be carried out, for example, by reacting the compound [IV] with hexaalkylditin (e.g., hexamethylditin) at a temperature of room temperature to 150 °C, preferably at a temperature of 80 °C to 110°C, in the presence of tetrakis (triphenylphosphine) palladium and an additive (e.g., LiCl) in an organic solvent.
  • the organic solvent can be selected from any one which does not disturb the coupling reaction, for example, dioxane, toluene, DME, DMF, H 2 0 or a mixture thereof.
  • the coupling reaction can be carried out by a conventional aryl coupling method, e.g., Stille coupling method (for reference of Stille coupling method: Stille et al., Angew. Chem . In t . Ed . Engl . , 25, 508 (1986))
  • the coupling reaction can be carried out, for example, at a temperature of room temperature to 150 °C, preferably at a temperature of 80°C to 120 °C, in the presence of tetrakis (triphenylphosphine) palladium in an organic solvent.
  • the organic solvent can be selected from any one which does not disturb the coupling reaction, for example, toluene, DME, DMF, H 2 O or a mixture thereof.
  • the compound [IV] may be prepared by condensing the compound of the formula [Ila] :
  • the compound [IV] may be also prepared by :
  • the conversion of the hydroxy group into trifluoromethanesulfonyloxy group can be carried out by using triflic anhydride at 0°C in the presence of a base (e.g., pyridine, NEt 3 , DIEA) in an organic solvent (e.g., CH 2 C1 2 , THF or a mixture thereof) .
  • a base e.g., pyridine, NEt 3 , DIEA
  • organic solvent e.g., CH 2 C1 2 , THF or a mixture thereof
  • the compound [III] may be prepared by:
  • the protecting group for the amino group can be selected from a conventional protecting group for an amino group, for example, a substituted or unsubstituted aryl- lower alkoxycarbonyl group (e.g., benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group) , a lower alkoxycarbonyl group (e.g., tert-butoxycarbonyl group) and the like.
  • a substituted or unsubstituted aryl- lower alkoxycarbonyl group e.g., benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group
  • a lower alkoxycarbonyl group e.g., tert-butoxycarbonyl group
  • the removal of the protecting group for the amino group can be carried out by a conventional method, which is selected according to the type of the protecting group to be removed, for example, catalytic reduction using a catalyst (e.g., palladium on activated carbon), treatment with an acid (e.g., TFA) and the like.
  • a catalyst e.g., palladium on activated carbon
  • an acid e.g., TFA
  • the condensation reaction can be carried out in a similar manner as described for the coupling reaction of the compound [IV] and [V] .
  • the compound [Via] wherein X 1 is trifluoromethanesulfonyloxy group may be prepared by reacting the compound of the formula [VIb] : wherein the symbols are the same as defined above with triflic anhydride in a similar manner as described for the preparation of the compound [IV].
  • the compound [V] may be prepared by a conventional method (e.g., reference (a) Kuivila et al . , J. Am. Chem. Soc, 1961, 83, 2159; (b) Gerrard, The Chemistry of Boron; Academic Press: New York, 1961; (c) Muetterties, The Chemistry of Boron and its Compounds: Wiley: New York, 1967; (d) Alamansa et al . , J. Am. Chem. Soc, 1994, 11 6, 11723-11736) :
  • the hydrolysis can be carried out at room temperature in an organic solvent (e.g., diethyl ether, THF or the mixture thereof) in the presence of mild acid (e.g., AcOH or citric acid) and water.
  • organic solvent e.g., diethyl ether, THF or the mixture thereof
  • mild acid e.g., AcOH or citric acid
  • the desired compound [I] of the present invention can be converted to each other.
  • Such conversion of the present compound [I] into the other compound [I] may be carried out in an organic solvent by selecting one of the following procedures (Procedure A to K) according to the type of the substituent thereof.
  • the organic solvent can be selected from any one which does not disturb the said procedure.
  • the compound [I] wherein R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a hydroxy-lower alkyl group such as a hydroxymethyl group or a group of the formula: lower alkyl-CH (OH) - can be prepared by the reduction of the compound [I] wherein the corresponding RJ R" , R 3 , R 5 or the substituent of the R 6 group is a carboxyl group, a formyl group or a group of the formula: lower alkyl-CO-.
  • the reduction reaction can be carried out by a conventional method using a reducing agent such as borane, alkali metal borohydride (e.g., sodium borohydride) and the like at a temperature of 0°C to room temperature in an organic solvent, e.g., methanol, ethanol, THF or the mixture thereof .
  • a reducing agent such as borane, alkali metal borohydride (e.g., sodium borohydride) and the like at a temperature of 0°C to room temperature in an organic solvent, e.g., methanol, ethanol, THF or the mixture thereof .
  • the compound [I] wherein R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a carboxyl group can be prepared by the oxidation of the compound [I] wherein the corresponding R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a formyl group.
  • the oxidation reaction can be carried out by a conventional method using an oxidizing agent, e.g., KMn0 4 and the like at a temperature of 0°C to 50°C, preferably at a temperature of 30°C to 50°C, in an organic solvent, e.g., acetone, H 2 0 or the mixture thereof.
  • the compound [I] wherein R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is an amino group or has an amino group can be prepared by the reduction of the compound [I] wherein the corresponding R 1 , R", R 3 , R 5 or the substituent of the R 6 group is a nitro group or has a nitro group.
  • the reduction reaction can be carried out by a conventional method, e.g., 1) a catalytic reduction using a catalyst such as Raney-nickel or a palladium on activated carbon and the like under a hydrogen atmosphere at room temperature in an organic solvent, e.g., methanol, H 2 0 or the mixture thereof, 2) chemical reduction using metal and inorganic acid, such as Fe/HCl, Sn/HCl, SnCl 2 /HCl and the like, or 3) reduction with a reducing agent, such as Na 2 S 2 0 , in a suitable solvent, e.g., methanol, ethanol, H 2 0 or the mixture thereof or without a solvent at a temperature of 0 °C to 80 °C .
  • a suitable solvent e.g., methanol, ethanol, H 2 0 or the mixture thereof or without a solvent at a temperature of 0 °C to 80 °C .
  • R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is an amino group or has an amino group
  • the compound [I] wherein R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is an amino group or has an amino group can be prepared by the deprotection of the amino group of the compound [I] wherein the corresponding R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 groups is an N- protected amino group or has an N-protected amino group and the protecting group is a conventional protecting group for an amino group, e.g., benzyloxycarbonyl group, tert- butoxycarbonyl group, 9-fluorenylmethoxycarbonyl group, allyl group and the like.
  • the deprotection reaction can be carried out by a conventional method, which is selected according to the type of the protecting group to be removed, e.g., 1) catalytic reduction using a catalyst such as palladium on activated carbon under a hydrogen atmosphere, 2) a treatment with an acid such as hydrogen chloride or TFA, 3) a treatment with an amine such as piperidine, 4) a treatment with a catalyst such as Wilkinson's catalyst, at room temperature or with heating in an organic solvent, e.g., CH 2 C1 2 , THF, MeOH, EtOH and MeCN, or without an organic solvent.
  • a catalyst such as palladium on activated carbon under a hydrogen atmosphere
  • an acid such as hydrogen chloride or TFA
  • amine such as piperidine
  • a treatment with a catalyst such as Wilkinson's catalyst
  • the deprotection reaction can be carried out by a conventional method, which is selected according to the type of the protecting group to be removed, e.g., a treatment with an acid such as TFA at a room temperature in an organic solvent, e.g., CH2CI 2 , or without an organic solvent.
  • a treatment with an acid such as TFA at a room temperature in an organic solvent e.g., CH2CI 2 , or without an organic solvent.
  • the deprotection reaction can be carried out by a conventional method, which is selected according to the type of the protecting group to be removed, for example, hydrolysis using a base (e.g., NaOH, LiOH, KOH) or an acid (e.g., hydrochloric acid) treatment with an acid (e.g., TFA), catalytic reduction using a catalyst (e.g., palladium on activated carbon) and the like, at room temperature in an organic solvent (e.g., MeOH, EtOH or THF) or without an organic solvent.
  • a base e.g., NaOH, LiOH, KOH
  • an acid e.g., hydrochloric acid
  • an acid e.g., TFA
  • catalytic reduction using a catalyst e.g., palladium on activated carbon
  • the compound [I] wherein R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a hydroxyl group or has a hydroxyl group can be prepared by the deprotection of the compound [I] wherein the corresponding R 1 , R ⁇ , R 3 , R 5 or the substituent of the R 6 group is a protected hydroxyl group or has a protected hydroxyl group and the protecting group is a conventional protecting group for a hydroxyl group, e.g., a methyl group, methoxymethyl group, tetrahydropyranyl group and the like.
  • the deprotection reaction can be carried out by a conventional method, which is selected according to the type of the protecting group to be removed, for example, a treatment with BBr 3 for the demethylation of a methoxy group, and a treatment with HC1 at a temperature of -78 °C to room temperature in an organic solvent, e.g., CH 2 CI 2 and MeOH for removal of methoxymethyl group.
  • a treatment with BBr 3 for the demethylation of a methoxy group for example, a treatment with BBr 3 for the demethylation of a methoxy group
  • HC1 at a temperature of -78 °C to room temperature in an organic solvent, e.g., CH 2 CI 2 and MeOH for removal of methoxymethyl group.
  • R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is an N-acylamino group, e.g., a lower alkanoylamino group, a lower alkoxycarbonylamino group, an arylcarbonylamino group, a chlorosulfonylcarbamoylamino group (such as 3- chlorosulfonylureido group) , a lower alkyl carbamoylamino group (such as 3- (lower alkyl) ureido group), a substituted or unsubstituted arylcarbamoyl amino group (such as 3- (substituted or unsubstituted aryl) ureido group), a (substituted or unsubstituted lower alkyl ) thiocarbamoylamino group (such as 3- (lower alkyl ) thiocarbamoylamino group (
  • the N- acylation reaction can be carried out by a conventional method using 1) an acylating reagent, e.g., a lower alkanoyl halide, a lower alkanoic acid anhydride, a lower alkyl halogenoformate such as a lower alkyl chloroformate, an aryl carbonyl halide, a chlorosulfonyl isocyanate, a lower alkyl isocyanate, a substituted or unsubstituted aryl isocyanate or a lower alkyl isocyanate, or 2) when preparing a lower alkoxycarbonylamino group, a (lower alkyl) carbamoylamino group, a substituted or unsubstituted arylcarbamoyl amino group, a (substituted or unsubstituted lower alkyl) thiocarbamoylamino group, a condensing reagent, e.
  • R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is an N- (lower alkylsulfonyl) amino group (e.g., methanesulfonylamino group), an N- (substituted or unsubstituted arylsulfonyl ) amino group (e.g., p-toluenesulfonylamino group, benzenesulfonylamino group) or an N- (substituted or unsubstituted heteroarylsulfonyl) amino group (e.g., quinolinosulfonylamino group) can be prepared by the N- sulfonylation of the compound [I] wherein the corresponding R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is an amino group.
  • N- (lower alkylsulfonyl) amino group e.g.
  • the N-sulfonylation reaction can be carried out by a conventional method using a lower alkylsulfonyl halide or a substituted or unsubstituted arylsulfonyl halide or a substituted or unsubstituted heteroarylsulfonyl halide in the presence of a base (e.g., pyridine, DMAP, Et 3 N, DIEA, NaHC0 3 , KHC0 3 , Na 2 C0 3 , K 2 C0 3 ) at a temperature of 0°C to room temperature, preferably at room temperature, in an organic solvent (e.g., CH 2 C1 2 , THF, DMF, CH 3 CN, toluene, acetone and the mixture thereof) .
  • a base e.g., pyridine, DMAP, Et 3 N, DIEA, NaHC0 3 , KHC0 3 , Na 2 C0 3 , K 2 C0 3
  • the compound [I] wherein R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a ureido group can be prepared by the hydrolysis of the compound [I] wherein the corresponding R 1 , R 2 , R 3 , R 5 or the substituent of the R 5 group is a 3-chlorosulfonylureido group.
  • the hydrolysis can be carried out using a base (e.g., LiOH, NaOH and the like) or an acid (e.g., HC1) at room temperature in a suitable solvent (e.g., THF, CH 3 CN, H 2 0) or a mixture thereof.
  • R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a substituted or unsubstituted lower alkoxy group, e.g., a substituted or unsubstituted hetero-cycloalkyl-lower alkoxy group (such as a substituted or unsubstituted piperidyl-lower alkoxy group, or a substituted or unsubstituted pyrrolidinyl-lower alkoxy group) , an aryl-lower alkoxy group, a heteroaryl- lower alkoxy group (such as a pyridyl-lower alkoxy group, a substituted or unsubstituted thiazolyl-lower alkoxy group, a substituted or unsubstituted isoxazolyl-lower alkoxy group, a substituted or unsubstituted thienyl-lower alkoxy group) , a lower alkoxy group, a
  • the alkylation reaction can be carried out using a halogenated lower alkane not having a substituent (e.g., methyl iodide) or that having a substituent such as a substituted or unsubstituted aryl group (e.g., unsubstituted aryl-lower alkyl halide such as benzyl bromide) , a substituted or unsubstituted heteroaryl group (e.g., substituted or unsubstituted heteroaryl-lower alkyl halide such as pyridylmethyl bromide, isoxazolylmethyl bromide, thiazolylmethyl bromide), a heterocycloalkyl group (e.g., substituted heterocycloalkyl-lower alkyl halide such as N- lower alkylpyrrolidmyl-lower alkyl bromide, N-lower alkylpiperidyl-lower alkyl bromide)
  • the alkylation reaction can be also carried out by using a conventional alkylation method such as Mitsunobu Reaction (for reference of Mitsunobu reaction: (a) Mitsunobu, Synthesis , 1-28, (1981), (b) Hughes, Organic Rea ctions , 42, 335 (1992), (c) Mitsuhashi et al., J. Am . Chem . Soc . , 94, 26 (1972) ) .
  • Mitsunobu Reaction for reference of Mitsunobu reaction: (a) Mitsunobu, Synthesis , 1-28, (1981), (b) Hughes, Organic Rea ctions , 42, 335 (1992), (c) Mitsuhashi et al., J. Am . Chem . Soc . , 94, 26 (1972) ) .
  • the compound [I] wherein R 1 , R 2 , R 3 , R 5 or the substituent of the R 5 group is a halogenated lower alkyl group can be prepared by the halogenation of the compound [I] wherein the corresponding R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a hydroxyl lower alkyl group.
  • the halogenation reaction can be carried out by the conventional method using, for example, a combination of tetrahalomethane (e.g., CBr 4 ) and triphenylphosphine at a room temperature in an organic solvent (e.g., CHC1 2 ) .
  • the compound [I] wherein R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a lower alkoxy-lower alkyl group can be prepared by reacting the compound [I] wherein the corresponding R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a halogenated lower alkyl group with an alkali metal lower alkoxide (e.g., sodium methoxide) at room temperature in an organic solvent (e.g., DMF, THF, CH 3 CN) .
  • an alkali metal lower alkoxide e.g., sodium methoxide
  • the compound [I] wherein R 1 , R 2 , R 3 , R 4 , R 5 or the substituent of the R 6 group is a substituted or unsubstituted carbamoyl group e.g., an N-lower alkylcarbamoyl group, an N,N- (lower alkyl) (lower alkyl) carbamoyl group, an N- (hydroxy-lower alkyl) carbamoyl group, an N- (morpholino-lower alkyl ) carbamoyl group, an N- (aryl- lower alkyl) carbamoyl group, an N- (lower alkanesulfonyl ) carbamoyl group, a hydroxycarbamoyl group, a carbamoyl group)
  • a substituted or unsubstituted carbamoyl group e.g., an N-lower alkylcarbamoyl group, an N,N- (lower
  • R 1 , R 2 , R 3 , R 4 , R 5 or the substituent of the R 6 group is a carboxyl group with a substituted or unsubstituted amine (e.g., a lower alkylamine, an N,N- (lower alkyl) (lower alkyl) amine, a
  • the condensation reaction can be carried out by the conventional method for a usual peptide synthesis as described for the condensing reaction of the compound [II] and [III] .
  • the reductive alkylation reaction can be carried out by the conventional method using a reductive agent (e.g., sodium cyanoborohydride) and an acid (e.g., HC1) at room temperature in an organic solvent (e.g., MeOH, THF, dioxane, or the mixture thereof).
  • a reductive agent e.g., sodium cyanoborohydride
  • an acid e.g., HC1
  • an organic solvent e.g., MeOH, THF, dioxane, or the mixture thereof.
  • the compound [I] wherein R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is an N, N-dimethylamino group can be prepared by the reductive alkylation of the compound [I] wherein the corresponding R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is an amino group.
  • the reductive alkylation can be carried out by the conventional method using formaldehyde, a reducing agent (e.g., sodium cyanoborohydride) and an acid (e.g., HC1) at room temperature in an organic solvent (e.g., MeOH, EtOH, THF, dioxane) or H 2 0 , or the mixture thereof.
  • the compound [I] wherein R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a lower alkokycarbonyl- ethenyl group can be prepared by the Wittig reaction of the compound [I] wherein the corresponding R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a formyl group.
  • the Wittig reaction can be carried out by the conventional method using, for example, ( triphenylphosphoranylidene) - acetic acid lower alkyl ester at a temperature of 50°C to 100°C in an organic solvent (e.g., toluene, THF).
  • the compound [I] wherein R 1 and R 5 are hydrogen atoms, R 2 and R 3 are halogen atoms, and R b is a phenyl group substituted by a lower alkoxy group and a lower alkyl group which is substituted by a group selected from the group consisting of a substituted or unsubstituted ammo group, a substituted or unsubstituted piperidmyl group, a substituted or unsubstituted morpholino group, a substituted or unsubstituted piperazmyl group and a substituted or unsubstituted pyrrolidmyl group can be prepared by reacting the compound [I] wherein R 1 and R 5 are hydrogen atoms, R 2 and R 3 are halogen atoms, and R D is a phenyl group substituted by a lower alkoxy group and a halogeno-lower alkyl group with a requisite amine such as a substituted or unsubstit
  • the compound wherein Z is sulfur atom can be prepared by reacting the compound [I] wherein Z is oxygen atom with Lawesson's reagent in a suitable organic solvent [ e . g . , toluene, xylene) at a temperature of 50 °C to 150 °C .
  • Procedure N Conversion of Carboxyl group to Tetrazolyl group
  • the compound [I] wherein R 1 , R 2 , R", R 4 , R 5 or the substituent of the R 6 group is a substituted or unsubstituted lower alkoxycarbonyl group can be prepared by condensing the compound [I] wherein the corresponding R 1 , R 2 , R 3 , R 4 , R 5 or the substituent of the R 6 group is a carboxyl group with a substituted or unsubstituted alcohol (e.g., a halogeno-lower alcohol, py ⁇ dyl-lower alcohol, a (lower alkylammo) -lower alcohol, a lower alkoxy-lower alcohol ) .
  • a substituted or unsubstituted alcohol e.g., a halogeno-lower alcohol, py ⁇ dyl-lower alcohol, a (lower alkylammo) -lower alcohol, a lower alkoxy-lower alcohol
  • the compound [I] wherein R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a lower alkyl group can be prepared by reducing the compound [I] wherein the corresponding R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a hydroxy-lower alkyl group.
  • the reduction can be carried out using a reducing reagent such as a silane compound (e.g., Et 3 S ⁇ H) in the presence of Lewis acid (e.g., BF 3 , T1CI 4 ) in a suitable organic solvent (e.g., MeCN, CH 2 C1 2 , THF) at a temperature of 0 °C to -78 °C .
  • a silane compound e.g., Et 3 S ⁇ H
  • Lewis acid e.g., BF 3 , T1CI 4
  • a suitable organic solvent e.g., MeCN, CH 2 C1 2 , THF
  • the compound [I] wherein R 6 is a substituted or unsubstituted halogeno-phenyl group can be prepared by reacting the compound [I] wherein R 6 is a substituted or unsubstituted phenyl group with halogenatmg reagent (e.g., Bu4NBr 3 , 3, 5-d ⁇ chloro-l-fluoropyridinium triflate) in a suitable solvent (e.g., MeCN, CH 2 C1 2 , THF) at room temperature or with heating.
  • halogenatmg reagent e.g., Bu4NBr 3 , 3, 5-d ⁇ chloro-l-fluoropyridinium triflate
  • a suitable solvent e.g., MeCN, CH 2 C1 2 , THF
  • the compound [I] wherein R 6 is a substituted or unsubstituted nitro-phenyl group can be prepared by reacting the compound [I] wherein R 6 is a substituted or unsubstituted phenyl group with HNO 3 in a suitable solvent (e.g., THF, NeCN, MeOH, EtOH) at a temperature of room temperature to 100 °C .
  • a suitable solvent e.g., THF, NeCN, MeOH, EtOH
  • the compound [I] wherein R° is a substituted or unsubstituted carbamoyl-phenyl group can be prepared by 1) reacting the compound [I] wherein R 6 is a substituted or unsubstituted phenyl group with chlorosulfonyl isocyanate and 2) hydrolyzing the obtained compound.
  • the reaction of the compound [I] and the isocyanate can be carried out in a suitable solvent (e.g., MeCN, CH 2 C1 2 , THF) at a temperature of 0 °C to room temperature.
  • the hydrolysis can be carried out with an acid (e.g., HC1, HN0 3 , H 2 S0 4 ) in a suitable solvent (e.g., MeCN, H 2 O) at a temperature of room temperature to 100 °C .
  • an acid e.g., HC1, HN0 3 , H 2 S0 4
  • a suitable solvent e.g., MeCN, H 2 O
  • the compound [I] wherein R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a (hydroxyimmo) -lower alkyl or (a lower alkoxyimmo) -lower alkyl group can be prepared by reacting the compound [I] wherein the corresponding R 1 , R 2 , R 3 , R 5 or the substituent of the R 6 group is a lower alkanoyl group with hydroxyamme or a lower alkoxyamme in a suitable solvent such as a lower alcohol (e.g., MeOH, EtOH, PrOH or BuOH) and MeCN, with a base such as alkali metal acetate (e.g., NaOAc) at room temperature or with heating .
  • a suitable solvent such as a lower alcohol (e.g., MeOH, EtOH, PrOH or BuOH) and MeCN, with a base such as alkali metal acetate (e.g., NaOAc) at room temperature or with
  • the compound [I] wherein R 1 , R 2 or R is a substituted or unsubstituted heterocyclic group can be prepared by reacting the compound [I] wherein the corresponding R 1 , R' or R 3 is halogen atom with a (substituted or unsubstituted heterocyclic) boronic acid using a conventional aryl coupling method such as Suzuki Coupling method.
  • the coupling reaction can be carried out following the procedure as describe in Method A.
  • Procedure V Oxidation of Sulfur Atom
  • a peracid e.g., mCPBA, H 2 0 2 , AcOOH, PhCOOOH
  • a suitable solvent e.g., CH 2
  • the compound [I] wherein RJ R 2 , R 3 or the substituent of the R 6 group is a lower alkyl group which is substituted by succinimido group or 2 , 5-d ⁇ oxo-l- ⁇ m ⁇ dazol ⁇ dmyl group optionally substituted by a lower alkyl group can be prepared by the imidation of the compound [I] wherein the corresponding R 1 , R 2 , R 3 or the substituent of the R° group is a hydroxy-lower alkyl group.
  • the imidation can be carried out by using a conventional method such as Mitsunobu Reaction (reference of Mitsunobu reaction is made in Procedure F) .
  • the reaction can be carried out by reacting the compound [I] with a di (lower alkyl) azodicarboxylate (e.g., diethyl azodicarboxylate) , a tri (lower alkyl)- or triarylphosphine (e.g., t ⁇ phenylphospphme) , and a requisite lmide (e.g., succmimide or hydantoin optionally substituted by a lower alkyl group), in a suitable organic solvent (e.g., Et 2 0 and THF) at a temperature of -20°C to 50°C.
  • a suitable organic solvent e.g., Et 2 0 and THF
  • the active ingredient of the present invention are exemplified by the following examples but not limited thereby .
  • Example 1 N- (2 , 6-D ⁇ chlorobenzoyl ) -4- (2-methoxyphenyl j -L- phenylalanme methyl ester (1A) and N-(2,6- Dichlorobenzoyl ) -4- (2-methoxyphenyl ) -L-phenylalanme (IB) .
  • Example 2 N- [ (S) -2-Phenylprop ⁇ onyl ] -4- (2-methoxyphenyl ) -L- phenylalanine .
  • Example 3 N- (2 , 6-Difluorobenzoyl) -4- (2, 6- dimethoxyphenyl) -L-phenylalanine .
  • Example 4 N- (2 , 6-D ⁇ chlorobenzoyl ) -4- (2-th ⁇ enyl ) -L- phenylalan e methyl ester (4A) and : N-(2,6- Dichlorobenzoyl) -4- (2-th ⁇ enyl) -L-phenylalanine (4B) .
  • Example 2 After usual work-up as shown in Example 1 the crude material was purified by flash column chromatography (silica gel; eluent: EtOAc/hexane 1:3) to yield N- (tert-butoxycarbonyl) -4- (2- thienyl) -L-phenylalanine methyl ester(1.81 g) .
  • ESMS m/z 362 (MH + ) .
  • Triflic anhydride (0.27 mL) was added slowly to an ice-cold solution of the product obtained above (0.5 g) in CH 2 C1 2 containing pyridine (0.33 mL) . The mixture was stirred for 2.5 h and was washed successively with water, 1 N HCl, satd. NaHC0 3 and water. The organic layer was dried
  • Pd(PPh 3 ) 4 (0.09 g) was added to a suspension of 2- methoxybenzene boronic acid (0.082 g) , K 2 CO 3 (0.16 g) and the product obtained above (0.214 g) in toluene/DMF (4 mL/0.4 mL) under N 2 .
  • the mixture was heated at 80 °C for 24 h, cooled, filtered and the solvent was evaporated. The residue was taken up with EtOAc, washed with water, dried (MgS0 4 ) and evaporated.
  • Example 6 N- (2 , 6-D ⁇ chlorobenzoyl) -3- [2-methoxyphenyl ) -DL- phenylalanine .
  • Example 7 N- (2 , 6-D ⁇ chlorobenzoyl) -4- (2 , 6- dimethoxyphenyl ) -L-phenylalanme methyl ester (7A) and N- (2, 6-D ⁇ chlorobenzoyl) -4- [2, 6-d ⁇ methoxyphenyl ) -L- phenylalanine (7B) .
  • Example 9 to- 14 The following compounds (Example 9 to- 14) were prepared by a procedure similar to the Example 7.
  • Example 10 N- (2 , 6-Dichlorobenzoyl ) -4- (2 , 3, 6- trimethoxyphenyl ) -L-phenylalanine.
  • ESMS m/z 504 (MH + ), 502 ([M-H] " ) .
  • N- (2, 6-Dichlorobenzoyl) -4- [2- [N- (tert- butyl) sulfamoyl] phenyl] -L-phenylalanine methyl ester 75 mg was dissolved in THF (5 mL) and to this solution was added a solution of LiOH (monohydrate, 10 mg) in water (0.4 mL) . Few drops of MeOH were added and the mixture was stirred at room temperature overnight. The mixture was evaporated, water was added to the resi ⁇ ue and the mixture was acidified with 10% citric acid. The separated solid was collected by filtration, washed with water and dried to give 60 mg of the title compound.
  • ESMS m/z 549 (MH + ) , 547 ( [M-H] " ) .
  • N- (2, 6-D ⁇ chlorobenzoyl) -4- [2- [N- (tert- butyl ) sulfamoyl] phenyl] -L-phenylalanme methyl ester 130 mg was dissolved in TFA (2 mL) , to this solution was added anisole (20 ⁇ M) and the mixture was stirred at room temperature for 6 h. TFA was removed under reduced pressure to give 100 mg of N- (2 , 6-d ⁇ chlorobenzoyl ) -4- (2- sulfamoylphenyl) -L-phenylalanine methyl ester.
  • ESMS m/z 507 (MH + ) .
  • N- (2, 6-D ⁇ chlorobenzoyl) -4- (2-sulfamoylphenyl ) -L- phenylalanme methyl ester 100 mg was dissolved in anhydrous pyridine (5 mL) . To this solution was added benzoyl chloride (50 ⁇ L) and the mixture was stirred for 12 h at room temperature under N 2 . EtOAc and satd. NaHC0 3 were added to the mixture and the EtOAc phase was washed with 1 N HCl, dried (MgS0 4 ) and evaporated.
  • Example 20 The following compounds (Examples 20 and 21) were prepared by a similar procedure and deprotection method as outlined in Examples 15 and 16, respectively.
  • N- (2, 6-Dichlorobenzoyl ) -4- (2-aminophenyl ) -L- phenylalanine methyl ester TFA salt (90mg) was dissolved in dry CH 2 C1 2 (5 mL) . To this solution was added Et 3 N (85 ⁇ L) and MsCl (30 ⁇ L) . The mixture was stirred at room temperature for 3 h and diluted with water. The organic phase was dried (MgS0 4 ) and evaporated to give N-(2,6- dichlorobenzoyl ) -4- [2- (methanesulfonylamino) phenyl] -L- phenylalanine methyl ester.
  • N- (2, 6-Dichlorobenzoyl) -4- (2-am ⁇ nophenyl ) -L- phenylalanine methyl ester TFA salt (90 mg) was dissolved in dry THF (5 mL) . Ac 2 0 (60 ⁇ L) and DIEA (160 ⁇ L) were added and the mixture was stirred at room temperature for 12 h. EtOAc was added and the resulting mixture was extracted with water. The organic phase was dried (MgS0 4 ) and evaporated to give N- (2, 6-dichIorobenzoyl) -4- [2- (acetylamino) ] phenyl ] -L-phenylalanine methyl ester.
  • N- (2, 6-Dichlorobenzoyl) -4- (2-aminophenyl) -L- phenylalanine methyl ester TFA salt (90 mg) was dissolved in THF (5 mL) and to this solution was added DIEA (160 ⁇ L) and CICOOMe (20 ⁇ L) . The mixture was stirred at room temperature for 12 h. After usual work-up as shown in Example 25, N- (2, 6-dichlorobenzoyl) -4- [2- (methoxycarbonylamino) phenyl] -L-phenylalanine methyl ester was obtained.
  • N-(2,6-Dichlorobenzoyl)-4- (2-aminophenyl ) -L- phenylalanine methyl ester TFA salt (90 mg) was dissolved in EtOH (5 mL) . To this solution was added formalin (96 ⁇ L), 1 N HCl (234 ⁇ L) and NaCNBH 3 (36 mg) . The mixture was stirred for 0.5 h at room temperature, then a 1:1 mixture of EtOH (0.5 mL) and IN HCl (0.5 mL) was added and the mixture was stirred overnight. Additional IN HCl was added and the mixture was stirred for 0.5 h. The mixture was neutralized with NaHC0 3 and extracted with EtOAc.
  • Example 28 N- (2 , 6-Dichlorobenzoyl ) -4- (2-ureidophenyl ) -L- phenylalanine .
  • N- (2, 6-Dichlorobenzoyl) -4- (2-aminophenyl ) -L- phenylalanine methyl ester TFA salt (90 mg) was dissolved in dry THF (5 mL) . To this solution was added chlorosulfonyl isocyanate (22 ⁇ L) and the mixture was stirred at room temperature for 2 h. The mixture was neutralized with NaHC0 3 and extracted with EtOAc. The combined organic extracts were dried (MgS ⁇ ) and evaporated .
  • Example 30 N- (2 , 6-Dichlorobenzoyl ) -4- (2-hydroxyphenyl ) -L- phenylalanine . 1) BBr (1 mL, 1M in CH 2 C1 2 ) was added to a CH 2 Cl 2 (10 mL) solution of N- (2 , 6-dichlorobenzoyl ) -4- (2- methoxyphenyl ) -L-phenylalanine methyl ester (0.215 g) at 0
  • N- (2, 6-Dichlorobenzoyl ) -4- (2, 6-dimethoxyphenyl ) -L- phenylalanine, ethyl ester (0.16 g, prepared in a fashion similar to that of the methyl ester described in Example 8) was dissolved in anhydrous CH 2 CI 2 (8 mL) .
  • the solution was cooled to -78 °C and BBr (0.56 mL, 1 M solution in CH 2 C1 2 ) was added.
  • the mixture was allowed to warm to 0 °C, and stirred at that temperature for 2 h.
  • the mixture was subsequently warmed to room temperature and quenched with satd. NaHC0 3 (5 mL) .
  • N- (2, 6-D ⁇ chlorobenzoyl ) -4- (2-formylphenyl) -L- phenylalanme methyl ester was synthesized by following the sequences similar to Example 1 but replacing 2-methoxy- benzeneboromc acid with 2-formylbenzeneboronic acid.
  • ESMS m/z 456 (MH + ) .
  • N- (2, 6-D ⁇ chlorobenzoyl ) -4- (2-formylphenyl ) -L- phenylalanine methyl ester (49.1 mg) was dissolved in a mixture of anhydrous MeOH (1 mL) and anhydrous THF (0.5 mL) .
  • Aniline (58.8 ⁇ L) , HCl (53.8 ⁇ L of 4M in dioxane) and 3A molecular sieves were then added and the mixture was stirred under N 2 at room temperature for 1 h.
  • NaCNBH 3 (4.06 mg) was added and the mixture was stirred for an additional 72 h. The pH of the mixture was brought to approximately 2 with IN HCl to quench the reaction.
  • Example 47 The following compounds (Examples 47 and 48) were prepared in a similar manner as described in Example 46.
  • N- (2, 6-D ⁇ chlorobenzoyl) -4- (2-formylphenyl ) -L- phenylalamne methyl ester (104 mg) was dissolved in acetone (700 ⁇ L) by warming up to about 40 °C .
  • a warm (40 °C) solution of KMn0 4 (61.2 mg) in a mixture of acetone (900 ⁇ L; and water (130 ⁇ L) was then added over a 1 h period and the resulting mixture was stirred at that temperature for an additional 2h.
  • the mixture was filtered through Celite and washed with acetone. The filtrate was taken up with water and acidified to approximately pH 2 with IN HCl, and extracted with EtOAc.
  • N- (2, 6-D ⁇ chlorobenzoyl ) -4- (2-carboxyphenyl ) -L- phenylalanine methyl ester (51.9 mg) was dissolved in anhydrous DMF (1 mL) and EDC (25.3 mg) , HOBT (20.2 mg) , DIEA (28.7 uL) and benzylamme (14.4 ⁇ L) were added. The resulting mixture was stirred at room temperature under N 2 for 20 h, diluted with EtOAc and washed with IN HCl, satd. NaHC0 3 , water and brine. The organic layer was dried (MgS ⁇ 4 ) and evaporated.
  • Example 54-59 were prepared in an analogous manner as described in Example 53.
  • Example 59 N- (2 , 6-Dichlorobenzoyl ) -4- [2- [N- (2- morpholinoethyl ) carbamoyl] phenyl] -L-phenylalanine .
  • ESMS m/z 570 (MH + ) .
  • Example 60 N- (2 , 6-Dichlorobenzoyl) -4- [2- ( carbamoyl ) phenyl ) ] -L-phenylalanine .
  • N- (2, 6-dichlorobenzoyl ) -4- (2-carboxyphenyl ) -L- phenylalanine methyl ester (52.6 mg) was dissolved in anhydrous THF (1 mL) , carbonyldiimidazole (36.1 mg) was added and the mixture was stirred at room temperature under N 2 for 2 h. Ammonium hydroxide (29% aqueous solution, 135 ⁇ L) was added and the mixture was stirred for an additional 22 h. The mixture was then extracted with EtOAc. The extract was washed with IN HCl, sat. NaHC0 3 and brine, dried (MgS0 4 ) and evaporated.
  • N- (2, 6-Dichlorobenzoyl ) -4- (2-carboxyphenyl ) -L- phenylalanine methyl ester (57.0 mg) was dissolved in anhydrous THF (1 mL) , carbonyldiimidazole (23.5 mg) was added and the mixture was stirred at room temperature under N 2 for 2 h. Methanesulfonamide (17.2 mg) and DBU (27 ⁇ L) were added and the mixture was stirred for an additional 18 h. The mixture was then heated to 40 °C, stirred for 7 h at the same temperature, cooled to room temperature, diluted with EtOAc, washed with IN HCl and then brine, dried (MgS0 4 ) and evaporated.
  • N- (2-Chloro-4-n ⁇ trobenzoyl) -4- (2-methoxyphenyl) -L- phenylalanine methyl ester was prepared in a similar fashion to that described in Example 1-1), 2), 3) and 4) but replacing 2 , 6-d ⁇ chlorobenzoyl chloride with 2-chloro-4- nitrobenzoyl chloride.
  • Example 64 N- [2-Chloro-4- (methanesulfonylamino) benzoyl] -4- (2 -methoxyphenyl) -L-phenylalanme .
  • Example 65 The following compounds (Examples 65-68) were prepared in an analogous manner as described in Example 64.
  • Example 65 N- [2-Chloro-4- (trifluoromethanesulfonylamino) benzoyl] -4- (2-methoxyphenyl) -L-phenylalanme .
  • ESMS m/z 557 (MH + ) .
  • MeS0 2 Cl was replaced by CF 3 S0 2 C1.
  • Example 66 N- [2-Chloro-4- (ethoxycarbonylamino) benzoyl ] -4- (2-methoxyphenyl) -L-phenylalanme.
  • ESMS m/z 497 (MH + ).
  • MeS0 2 Cl was replaced by EtOCOCl .
  • 3-Acetyl-L-tyros ⁇ ne ethyl ester was prepared by bubbling HCl gas into a solution of 3-acetyl-L-tyrosme (5 g) in ethanol (30 mL) .
  • Di-tert-butyl dicarbonate (5 g) was added to a solution of 3-acetyl-L-tyrosme ethyl ester
  • Example 72 3-Acetyl-N- (2 , 6-dichlorobenzoyl ) -4-phenyl-L- phenylalanine .
  • 2-methoxybenzeneboron ⁇ c acid By substituting 2-methoxybenzeneboron ⁇ c acid with benzeneboronic acid, the title compound was obtained as a solid in a similar manner as described in Example 71. mp. 109-111 °C; MS: m/z 456 (MH + ) .
  • Example 75 N- (2 , 6-Dichlorobenzoyl ) -3-methoxy-4- (2- methoxyphenyl ) -L-phenylalanine.
  • Example 135 N- (2, 6-Dichlorobenzoyl ) -A - (2, 6-difluorophenyl ; L-phenylalanine .
  • N- (2, 6-Dichlorobenzoyl) -O- (trifluoromethanesulfonyl) -L-tyrosine methyl ester was prepared in a similar method as described in Example 5-1) and 2) .
  • Example 136 - 140 The following compounds (Example 136 - 140) were prepared in a similar procedure as described in Example 135 but replacing l-bromo-2, 6-difluorobenzene with the requisite bromobenzenes . TABLE 9
  • Example 141-146 The following compounds (Example 141-146) were prepared in a similar method as described in Example 5 but replacing 2-methoxybenzeneboronic acid with the requisite benzeneboronic acids.
  • Example 147-149 The following compounds (Example 147-149) were prepared a similar method as described in Example 7 but replacing -dimethoxybenzene with the requisite benzenes.
  • Example 150 N- (2, 6-Dichlorobenzoyl) -4- (2-cyano-6- carbamoylphenyl) -L-phenylalanine .
  • Example 151 N- (2, 6-Dichlorobenzoyl) -A - (2, 6-dicyanophenyl) - L-phenylalanine .
  • Example 153 N- (2, 6-Dichlorobenzoyl ) -4- (2, 6-dimethoxy-3- fluorophenyl) -L-phenylalanine (153A) and N-(2,6- dichlorobenzoyl) -4- (2, 6-dimethoxy-3, 5-difluorophenyl) -L- phenylalanine (153B)
  • N- (2, 6-Dichlorobenzoyl ) -4- (2, 6-dimethoxyphenyl ) -L- phenylalanine methyl ester (232 mg) was dissolved in anhydrous MeCN (10 mL) under N 2 and 3, 5-dichloro-l- fluoropyridinium triflate (85%, 353 mg) was added and the mixture was refluxed for 1 day. More 3 , 5-dichloro-l- fluoropyridinium triflate (175 mg) was added and the mixture was refluxed for another day. The mixture was then concentrated, and the residue was taken up with water and extracted with CH2CI2. The extract was washed with sat.
  • N- (2, 6-D ⁇ chlorobenzoyl) -4- [4- [ (N-allyl-N-tert- butoxycarbonylammo) -2, 6-d ⁇ methoxyphenyl] -L-phenylalanine methyl ester (1.25 g) was dissolved in CH2CI2 (10 mL) and TFA (10 mL) was added and the mixture was stirred under N 2 at room temperature for 1.5 h. The mixture was evaporated and the residue was taken up with CH2CI2, washed with sat. NaHC0 3 , dried (MgS0 4 ), filtered and evaporated.
  • N- (2, 6-Dichlorobenzoyl) -4- (4-allylamino-2 , 6- dimethoxyphenyl) -L-phenylalanine methyl ester (0.93 g) was dissolved in MeCN/water (40 mL of 84:16) under N 2 .
  • Wilkinson's catalyst (79 mg) was added and the mixture was brought to boiling. After 2 h, more catalyst (170 mg) was added and the reaction continued for another 6 h. The solvent was evaporated and the residual water coevaporated with MeCN. The residue was purified by preparative TLC
  • Example 166-171 The following compounds (Example 166-171) were prepared in a similar method as described in Example 53, using N- (2, 6-dichlorobenzoyl) -A - ( 4-carboxy-2 , 6-dimethoxyphenyl ) -L- phenylalanine methyl ester and an appropriate amine.
  • N- (2, 6-Dichlorobenzoyl) -4- (2, 6-dimethoxy-3- methoxymethoxyphenyl) -L-phenylalanine methyl ester (165 mg) was dissolved in MeOH (5 mL) and HCl in dioxane (4 M, 1 mL) was added to the mixture. The mixture was stirred at room temperature for 3 h. The mixture was evaporated and the residue was taken up with water (40 mL) and extracted with CH 2 C1 2 . The extract was dried (MgS0 4 ), filtered and evaporated.
  • N- [2-Chloro-4- (tert-butoxycarbonyl) benzoyl] -4- (2- methoxyphenyl ) -L-phenylalanine methyl ester (305 mg) was dissolved in anhydrous CH 2 C1 2 (2 mL) under N 2 and TFA (2 mL) was added. The mixture was stirred at room temperature for 2 h to give N- [2-chloro-4-carboxybenzoyl] -4- (2- methoxyphenyl) -L-phenylalanine methyl ester (315 mg) .
  • Example 187 N- [2-Chloro-4- [ [ (4- trifluoromethylphenyl) sulfonyl] amino] benzoyl] -4- (2- methoxyphenyl) -L-phenylalanine; ESMS m/Z 655 (M + +Na), 633 (MH + ) , 631 (M-H) " .
  • Example 188 N- [2-Chloro-4- (tosylamino) benzoyl] -4- (2- methoxyphenyl) -L-phenylalanine; ESMS m/z 601 (M + +Na), 579 (MH + ) , 577 (M-H) " .
  • Example 189 N- [2-Chloro-4- [ [ (4- fluorophenyl) sulfonyl] amino] benzoyl] -4- (2-methoxyphenyl ) -L- phenylalanine; ESMS m/z 605 (M + +Na), 583 (MH + ) , 581 (M-H) " .
  • Example 190 N- [2-Chloro-4- [ [ (4- methoxyphenyl) sulfonyl] amino] -benzoyl] -4- (2-methoxyphenyl ) -
  • Example 192 N- [2-Chloro-4- [ [ (2- methylphenyl) sulfonyl] amino] benzoyl] -4- (2-methoxyphenyl) -L- phenylalanine; ESMS m/z 601 (M + +Na) , 579 (MH + ) , 577 (M-H) " .
  • Example 193 N- [2, 6-Dichloro-4- [ (2- thienylsulfonyl) amino] benzoyl] -4- (2 , 6-dimethoxyphenyl) -L- phenylalanine; mp . 141-142 °C . ESMS m/Z 635 (MH + ) .
  • Example 199-204 The following compounds (Examples 199-204) were prepared in a similar manner as described in Examples 64, 69 or 70.
  • Example 205 N- (4-Ureido-2, 6-dichlorobenzoyl) -4- (3- carbamoyl-2, 6-dimethoxyphenyl) -L-phenylalanine
  • Example 206 N- ( 4-Amino-2 , 6-dichlorobenzoyl ) -4- (2 , 6- dimethoxyphenyl ) -L-phenylalanine
  • Example 207-208 The following compounds (Examples 207-208) were prepared in a similar method as described in Example 2.
  • Example 209-212 The following compounds (Example 209-212) were prepared in a similar manner as described in Example 1 and 2 but replacing 2, 6-dichlorobenzoyl chloride and (S)-2- phenylpropionic acid with requisite benzoyl chlorides and benzoic acids .
  • Example 214-217 The following compounds (Examples 214-217) were prepared in a similar procedure as described in Example 4.
  • Example 214 N- (2, 6-Dichlorobenzoyl) -4- (2-formyl-3- thienyl) -L-phenylalanine; ESMS m/z 470 (M + +Na) , 448 (MH + ) , 446 (M-H) " .
  • Example 215 N- (2 , 6-Dichlorobenzoyl) -4- (5-acetyl-2-thienyl) - L-phenylalanine: mp . 194-195 °C .
  • Example 217 N- (2, 6-Dichlorobenzoyl ) -4- ( 4-pyridyl) -L- phenylalanine: ESMS m/z 415 (MH + ) .
  • Example 220 N- (2 , 6-Dichlorobenzoyl) -4- [2 , 6-dimethoxy-4- (3- thienylmethoxy) phenyl] -L-phenylalanine; ESMS m/z 584 (M-H) " .
  • Example 221 N- (2, 6-Dichlorobenzoyl) -4- [2, 6-dimethoxy-4- [ (2, 6-dichlorophenyl ) methoxy] phenyl] -L-phenylalanine; ESMS m/z 672 (M + +Na), 648 (M-H) " .
  • Example 222 N- (2, 6-Dichlorobenzoyl) -4- [2, 6-dimethoxy-4- (2- hydroxyethoxy) phenyl] -L-phenylalanine; ESMS m/z 556 (M + +Na), 534 (MH + ) , 532 (M-H) " .
  • Example 223 N- (2, 6-Dichlorobenzoyl) -4- [2, 6-dimethoxy-4- [2- (N, N-dimethylamino) ethoxy] phenyl] -L-phenylalanine : ESMS m/z 561 (MH + ) .
  • Example 224 N- (2, 6-Dichlorobenzoyl) -4- (3-i-propoxyphenyl) - L-phenylalanine; ESMS m/z 494 (M + +Na), 472 (MH + ) , 470 (M-H) " .
  • Example 225 N- (2 , 6-D ⁇ chlorobenzoyl ) -4- (2-i-propoxyphenyl ) - L-phenylalanine; ESMS m/z 494 (M + +Na), 472 (MH”) , 470 (M-H) " .
  • Example 226 N- (2, 6-Dichlorobenzoyl) -4- (2-i-propyloxy-6- methoxyphenyl) -L-phenylalanine; ESMS m/z 524 (M + +Na), 500 (M-H) ⁇ .
  • Example 228 N- ( 2 , 6-Dichlorobenzoyl ) -4 - [ 6-methoxy-2- ( 2 - f luoroethoxy) phenyl ] -L-phenylalanine .
  • the title compound was prepared in a similar method as described in Example 227 but replacing 2-bromoethylacetate with 2-fluoroethyl bromide. mp 206 -207 °C; ESMS m/Z 506 (MH + ) .
  • Example 229-232 The following compounds (Examples 229-232) were prepared in a similar procedure as described in Example 227 using requisite benzeneboronic acid.
  • Example 233-241 The following compounds (Examples 233-241) were obtained in a similar manner as described in Example 228 using requisite benzeneboronic acid.
  • Example 233 N- (2, 6-Dichlorobenzoyl) -4- [2, 3-methylenedioxy- 6- (2-methoxyethoxy) phenyl] -L-phenylalanine . mp 167-168 °C; ESMS m/Z 532 (MH + ) .
  • Example 234 N- (2 , 6-Dichlorobenzoyl) -4- [2 , 3-methylenedioxy- 6- [2- (N, N-dimethylamino) ethoxy] phenyl] -L-phenylalanine; ESMS m/z 545 (MH + ) , 543 (M-H) " .
  • Example 235 N- (2, 6-D ⁇ chlorobenzoyl) -4- [2 , 3-methylened ⁇ oxy- 6- (methoxymethoxy) phenyl] -L-phenylalanme; ESMS m/z 518 (MH + ) , 516 (M-H) " .
  • Example 236 N- (2, 6-D ⁇ chlorobenzoyl) -4- (2, 3-methylened ⁇ oxy- 6-hydroxyphenyl) -L-phenylalanme; ESMS m/z 474 (MH + ) .
  • Example 237 N- (2, 6-D ⁇ chlorobenzoyl) -4- (2, 3-methylened ⁇ oxy- 6-ethoxyphenyl) -L-phenylalanme; ESMS m/z 502 (MH + ) .
  • Example 238 N- (2, 6-D ⁇ chlorobenzoyl) -4- [2, 3-methylened ⁇ oxy- 6- (2-hydroxyethoxy) phenyl] -L-phenylalanme; ESMS m/z 518 (MH + ) , 516 (M-H) " .
  • Example 239 N- (2, 6-D ⁇ chlorobenzoyl) -4- [2, 3-methylened ⁇ oxy- 6- (cyanomethoxy) phenyl] -L-phenylalanme; ESMS m/z 513 (MH + ) .
  • Example 240 N- (2 , 6-D ⁇ chlorobenzoyl) -4- (2, 3-methylened ⁇ oxy- 6-methoxyphenyl) -L-phenylalanme; ESMS m/z 488 (MH + ) .
  • Example 241 N- (2 , 6-D ⁇ chlorobenzoyl ) -4- (2 , 3-ethylened ⁇ oxy-6- methoxyphenyl) -L-phenylalanme: ESMS m/z 502 ⁇ MY) . mp . 218 °C.
  • Example 242 N- (2, 6-D ⁇ chlorobenzoyl) -4- [2, 6-d ⁇ methoxy-4- [ (methylammo) methyl] phenyl] -L-phenylalanme (TR-14454 )
  • Example 243-252 The following compounds (Examples 243-252) were prepared in an analogous manner as described in Example 242 by replacing MeNH 2 with the requisite amines. TABLE 18
  • Example 254-261 The following compounds (Example 254-261) were prepared in a similar manner as described in Example 242 or 253 from requisite starting materials.
  • Example 256 N- (2 , 6-Dichlorobenzoyl ) -4- [2 , 6-dimethoxy-4- (piperidinomethyl) phenyl] -L-phenylalanine; ESMS: m/z 571 (MH + )
  • Example 258 N- (2 , 6-Dichlorobenzoyl ) -4- [2, 6-dimethoxy-4- [ (4- benzyl-1-piperazmyl) methyl] phenyl] -L-phenylalanine; ESMS : m/z 662 (MH + )
  • Example 259 N- (2, 6-Dichlorobenzoyl) -4- [2 , 6-dimethoxy-4- [ (N, N-dimethylamino) methyl] phenyl] -L-phenylalanine ethyl ester hydrochloride; ESMS: m/z 560 (MH + ) ; mp. 146.5 °C .
  • Example 260 N- (2 , 6-Dichlorobenzoyl) - A - [ 2 , 6-dimethoxy-4- (piperidinomethyl) phenyl] -L-phenylalanine ethyl ester hydrochloride; ESMS: m/z 600 (MH + ) ; mp . 205.5 °C .
  • Example 261 N- (2, 6-Dichlorobenzoyl) -4- [2 , 6-dimethoxy-4- (morpholinomethyl) phenyl] -L-phenylalanine ethyl ester hydrochloride; ESMS: m/z 601 (MH + ) ; mp . 177.5 °C .
  • Example 263 N- (2, 6-Dichlorobenzoyl) -4- [2 , 6-dimethoxy-4- ( thiomorpholinomethyl) phenyl] -L-phenylalanine S-oxide (263B) and N- (2, 6-dichlorobenzoyl) -A - [ 2 , 6-dimethoxy-4-
  • N- (2 , 6-dichlorobenzoyl) -4- [2, 6- dimethoxy-4- ( thiomorpholinomethyl ) phenyl ] -L-phenylalanine ethyl ester (0.1 g) in CH 2 C1 2 (3 mL) at -10 °C under N 2 was added mCPBA ( 40 mg) and the mixture was stirred for 2 h. The mixture was diluted with CH 2 CI 2 , washed with satd. NaHC0 3 and brine, dried, evaporated and purified by a preparative TLC to give N- (2 , 6-dichlorobenzoyl) -4- [2 , 6-dimethoxy-4-
  • Example 264 N- (2 , 6-Dichlorobenzoyl) -4- [2 , 6-dimethoxy-4- [2- (4 -methyl-1-piperazinyl) ethyl] phenyl] -L-phenylalanine.
  • Example 266 N- (2, 6-Dichlorothiobenzoyl ) -4- (2, 6- dimethoxyphenyl ) -L-phenylalanine
  • Example 268 N- (2, 6-dichlorobenzoyl) -4- (2 , 6- dimethoxyphenyl ) -L-phenylalanine N-hydroxyamide .
  • Example 269 N- (2, 6-Dichlorobenzoyl) -4- (2-methoxyphenyl) -L- phenylalanine N-hydroxyamide.
  • Example 270 ( IS) -N- (2 , 6-Dichlorobenzoyl) -2- [4- (2, 6- dimethoxyphenyl) phenyl] -1- (lH-tetrazol-5-yl) ethylamine .
  • Ph P (0.21 g) was added to a solution of the product obtained above (0.17 g) in MeCN ( 10 mL) .
  • the mixture was cooled to 0 °C, and DIAD (0.16 mL) and TMSN 3 (0.11 mL) was added.
  • the mixture was allowed to warm to room temperature, heated to 40 °C for 1 h, cooled to room temperature and stirred overnight.
  • the mixture was partitioned between EtOAc and water. The organic layer was washed with satd. NaHC0 3 followed by brine, dried (MgS0 4 ) , filtered and evaporated.
  • Example 271-274 The following compounds (Example 271-274) were prepared in a similar procedure as described in Example 270-1) .
  • Example 271 N- (2 , 6-Dichlorobenzoyl) -4- (2, 6- dimethoxyphenyl) -L-phenylalanine 2- (dimethylamino) ethyl ester; ESMS: m/z 582 (MH + ) .
  • Example 272 N- (2 , 6-Dichlorobenzoyl ) -4- (2, 6- dimethoxyphenyl) -L-phenylalanine 2-pyridylmethyl ester; ESMS: m/z 582 (MH + ) .
  • Example 273 N- (2 , 6-Dichlorobenzoyl ) -4- (2 , 6- dimethoxyphenyl) -L-phenylalanine 3-pyridylmethyl ester; ESMS: m/z 582 (MH + ) .
  • Example 274 N- (2 , 6-Dichlorobenzoyl ) -4- (2 , 6- dimethoxyphenyl ) -L-phenylalanine 4-pyridylmethyl ester; ESMS: m/z 582 (MH + ) .
  • Example 275 N- (2, 6-Dichlorobenzoyl ) -4- (2 , 6- dimethoxyphenyl ) -L-phenylalanine i-propyl ester.
  • HCl gas was bubbled into a solution of N-(2,6- dichlorobenzoyl ) -A - (2, 6-dimethoxyphenyl) -L-phenylalanine (0.15 g) in THF/2-propanol (2/5 mL) for 15 min and the solution was stirred overnight at room temperature.
  • the mixture was saturated with HCl gas, allowed to stand overnight at room temperature, and evaporated. The residue was partitioned between EtOAc and water.
  • Examples 277-286 were prepared in a similar method as described in Example 1 or Example 2, replacing 2 , 6-dichlorobenzoic acid or 2,6- benzoyl chloride with an appropriate substituted benzoic acid or acid chloride thereof.
  • Example 287-290 The following compounds (Examples 287-290) were prepared in an analogous manner as described in Example 2 by replacing (S) -2-phenylpropionic acid with properly substituted 2-chlorobenzoic acids. TABLE 2 0
  • Example 291 N- [2-Chloro-4- (2-hydroxymethyl-l- pyrrolyl) benzoyl] -4- (2-methoxyphenyl) -L-phenylalanine.
  • Example 292-293 The following compounds (Example 292-293) were prepared in a similar method as described in Example 2 TABLE 2 1
  • N- ( 9-Fluorenylmethoxycarbonyl) -3- (5-bromo-2- thienyl) -L-alanine 813 mg was dissolved in EtOH (15 mL) and HCl (gas) was bubbled through the solution for 5 min at 0°C. The mixture was warmed to 50 °C and stirred for 1 h. After cooling to room temperature the solvent was evaporated.
  • Example 296 N- (2 , 6-Dichlorobenzoyl ) -3-ethyl-4- (2- methoxyphenyl ) -L-phenylalanine.
  • Example 297 N- (2 , 6-Dichlorobenzoyl) -4- (2 , 6- dimethoxyphenyl) -3-acetylamino-L-phenylalanine .
  • N- (2, 6-Dichlorobenzoyl) -4- (2, 6-dimethoxyphenyl ) -3- nitro-L-phenylalanine ethyl ester was prepared in a similar manner as described in Example 1 by replacing N-(tert- butoxycarbonyl ) -L-tyrosme ethyl ester with N-tert- butoxycarbonyl-3-n ⁇ tro-L-tyrosme ethyl ester.
  • Example 298-300 were prepared in a similar method as described in Example 297.
  • Example 300 N- (2 , 6-dichlorobenzoyl) -3- (2-oxo-l- pyrrolidinyl ) -4- (2, 6-dimethoxyphenyl) -L-phenylalaine
  • Examples 301-302 were prepared in a similar manner as described in Example 2 by replacing 2-phenylprop ⁇ on ⁇ c acid with the requisite benzoic acid and replacing 4- (2-methoxyphenyl) -L-phenylalanme methyl ester hydrochloride with 4- (2 , 6-d ⁇ methoxyphenyl) -L- phenylalanme methyl ester hydrochloride .
  • Example 301 N- (2, 6-D ⁇ chloro-4-phenylbenzoyl) -4- (2, 6- dimethoxyphenyl) -L-phenylalanine : ESMS: m/z 550 (MH + ) ; mp. 215 °C.
  • Example 302 N- [2, 6-D ⁇ chloro-4- ( l-methyl-2- pyrrolyl) benzoyl] -A - (2, 6-d ⁇ methoxyphenyl) -L-phenylalanme .
  • Example 303 N- [4- (2-Pyrrolyl) -2, 6-d ⁇ chlorobenzoyl] -4- (2 , 6- dimethoxyphenyl ) -L-phenylalanme .
  • N- (4-Bromo-2, 6-d ⁇ chlorobenzoyl) -A - (2, 6- dimethoxyphenyl) -L-phenylalanme methyl ester (0.410 g) was coupled with l-tert-butoxycarbonyl-2-pyrroleboron ⁇ c acid (0.930 g) in THF (10 mL) as described in Example 7-2) to give 0.435 g of N- [4- ( l-tert-butoxycarbonyl-2-pyrrolyl) -2 , 6- dichlorobenzoyl] -4- (2, 6-d ⁇ methoxyphenyl ) -L-phenylalanme methyl ester.
  • ESMS m/z 653 (MH ) .
  • Example 304 N- [4- (5-Pyrazolyl) -2, 6-d ⁇ chlorobenzoyl) -4- (2, 6-d ⁇ methoxyphenyl) -L-phenylalanme.
  • Example 306 N- [4- ( 1, 3-thiazol-2-yl) -2 , 6-dichlorobenzoyl] - 4- (2, 6-dimethoxyphenyl) -L-phenylalanine.
  • Example 307 N- [ 4- ( 1, 3-Thiazol-4-yl) -2 , 6-dichlorobenzoyl] - 4- (2, 6-dimethoxyphenyl) -L-phenylalanine.
  • Example 308 N- [4- (2-Pyrazinyl) -2 , 6-dichlorobenzoyl ] -4- (2, 6-dimethoxyphenyl) -L-phenylalanine .
  • Example 309-318 were prepared in a similar method as described in Example 303.
  • N- (2, 6-D ⁇ chlorobenzoyl) - A - (2, 6-d ⁇ methoxyphenyl ) -L- phenylalanme methyl ester (1.59 g) was dissolved in THF (4 mL) under N 2 then 70% HN0 3 (4 mL) was added and the mixture was stirred at 50 °C overnight. The mixture was diluted with AcOEt (150 mL) and washed with water (100 mL) . The organic layer was dried (MgS0 4 ), filtered and evaporated. The residue was dissolved m anhydrous MeOH (100 mL) and dry HCl gas was bubbled through the mixture at 0 °C for a few minutes.
  • Example 324 N- (2 , 6-D ⁇ chlorobenzoyl ) -4- [2 , 6-d ⁇ methoxy-3- (methylureido) phenyl] -L-phenylalanme
  • the title compound was obtained in a similar procedure as described in Example 70 by reacting N-(2,6- dichlorobenzoyl ) -4- (2, 6-d ⁇ methoxy-3-ammo ⁇ henyl ) -L- phenylalanine methyl ester with MeNCO instead of MeNCS.
  • MS m/z 546 (MH + ) mp . 236-237 °C .
  • N- (2, 6-D ⁇ chlorobenzoyl ) -4- (2, 6-d ⁇ methoxyphenyl ) -L- phenylalanme methyl ester 150 mg was dissolved in MeCN (6 mL) under N 2 and chlorosulfonyl isocyanate (45 ⁇ L) was added, and the mixture was stirred at room temperature for 2.5 h. The mixture was concentrated and IN HCl (8 mL) was added. The mixture was stirred at room temperature overnight, extracted with AcOEt, dried (MgS0 4 ), filtered and evaporated.
  • Example 327-328 The following compounds (Examples 327-328) were made from 7-bromo-2 , 3-d ⁇ hydrobenzo [ b] furan and 8-bromo-3,4- d ⁇ hydro-2H-benzopyran respectively (Kerrigan, F. , Martin, C, Thomas, G. H., let . Lett . 1998, 39, 2219-2222), in a similar procedure as described in Example 7.
  • Example 334 The title compound was prepared in a similar method as described in Example 322. MS m/z 553 (MH + ) , mp . 234.8 °C . The following compounds (Examples 332-335) were prepared in a similar method as described in Example 2.
  • Example 336 N- (2 , 6-Dichlorobenzoyl ) -3-chloro-4- (2- methoxyphenyl ) -L-phenylalanine
  • Example 340-342 The following compounds (Examples 340-342) were prepared in a similar method as described in Example 73.
  • Example 343 N- (2 , 6-Dichlorobenzoyl ) -3-acetylamino-4- phenyl-L-phenylalanine The title compound was prepared in a similar procedure as described in Example 80. ESMS m/z 471 (MH + ) .
  • Examples 344-345) were prepared in a similar procedure as described m Example 64 using ethyl chloroformate .
  • Example 347-350 The following compounds (Examples 347-350) were prepared in a similar procedure as described in Example 32.
  • Example 358 N- (2 , 6-D ⁇ chlorobenzoyl) -4- (2 , 6-d ⁇ methoxy-4- [ (3-methy1-2 , 5-d ⁇ oxo-l- ⁇ m ⁇ dazol ⁇ dmyl ) ethyl] phenyl] -L- phenylalanine

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Abstract

L'invention se rapporte à une composition pharmaceutique comprenant en tant que composant actif le composé correspondant à la formule suivante: (1) dans laquelle Le cycle A est un cycle aromatique ou hétérocyclique; Q est une liaison carbonyle, alkylène inférieur, alcénylène inférieur, -O-(alkylène inférieur)-, etc.; n est 0, 1 ou 2; Z est oxygène ou soufre; W est oxygène, soufre, -CH=CH-, NH- ou -N=CH-; R?1, R2 et R3¿ sont identiques ou différents et sont hydrogène, halogène, hydroxyle, groupe alkyle inférieur substitué ou non substitué, groupe alcoxy inférieur substitué ou non substitué, groupe amino substitué ou non substitué; R4 est tétrazolyle, groupe carboxyle, amide ou ester; R5 est hydrogène, nitro, amino, hydroxyle, alcanoyle inférieur, alkyle inférieur, etc.; R6 est sélectionné entre (a) un groupe phényle substitué ou non substitué, (b) un groupe pyridyle substitué ou non substitué, (c) un groupe thiényle substitué ou non substitué ou (d) un groupe benzofuranyle substitué ou non substitué, etc.; ou à un sel pharmaceutiquement acceptable de ce composé.
PCT/US1999/000993 1998-01-20 1999-01-19 INHIBITEURS DE L'ADHESION CELLULAIRE A MEDIATION PAR α4 WO1999036393A1 (fr)

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EP99904115A EP1049662B1 (fr) 1998-01-20 1999-01-19 Inhibiteurs de l'adhesion cellulaire a mediation par alpha 4
SG200204434A SG118147A1 (en) 1998-01-20 1999-01-19 Inhibitors of alpha4 mediated cell adhesion
AU24584/99A AU749568B2 (en) 1998-01-20 1999-01-19 Inhibitors of alpha4 mediated cell adhesion
CA002318527A CA2318527C (fr) 1998-01-20 1999-01-19 Inhibiteurs de l'adhesion cellulaire a mediation par .alpha.4
NZ506081A NZ506081A (en) 1998-01-20 1999-01-19 Inhibitors of alpha-4 mediated cell adhesion
DE69932032T DE69932032T2 (de) 1998-01-20 1999-01-19 Inhibitoren der alpha4 vermittelten zelladhäsion
BRPI9907040-5A BR9907040B1 (pt) 1998-01-20 1999-01-19 composto derivado de l-fenilalanina como inibidor de adesão celular mediada por integrina alfa4, composição farmacêutica, uso do composto, e, processo para prepará-lo.
JP2000540111A JP3634749B2 (ja) 1998-01-20 1999-01-19 α４介在細胞接着阻害剤
IL13738599A IL137385A0 (en) 1998-01-20 1999-01-19 INHIBITORS OF α4 MEDIATED CELL ADHESION
US09/619,712 US6521666B1 (en) 1998-01-20 2000-07-19 Inhibitors of α4 mediated cell adhesion
IL137385A IL137385A (en) 1998-01-20 2000-07-19 Inhibitors of α4-induced cell coupling
HK01100247A HK1029979A1 (en) 1998-01-20 2001-01-10 Inhibitors of alpha4 mediated cell adhesion alpha 4
US10/286,777 US6855843B2 (en) 1998-01-20 2002-11-04 Inhibitors of α4 mediated cell adhesion
CY20061100959T CY1105433T1 (el) 1998-01-20 2006-07-10 ΑΝΑΣΤΟΛΕΙΣ ΜΙΑΣ α4 ΔΙΑΜΕΣΟΛΑΒΟΥΜΕΝΗΣ ΣΥΓΚΟΛΛΗΣΗΣ ΚΥΤΤΑΡΩΝ

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AR (1) AR014448A1 (fr)
AT (1) ATE330935T1 (fr)
AU (1) AU749568B2 (fr)
BR (1) BR9907040B1 (fr)
CA (1) CA2318527C (fr)
CY (1) CY1105433T1 (fr)
DE (1) DE69932032T2 (fr)
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HK (1) HK1029979A1 (fr)
IL (2) IL137385A0 (fr)
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Cited By (82)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999049856A3 (fr) * 1998-03-27 1999-11-18 Genentech Inc Antagonistes destines au traitement de troubles induits par le recepteur d'adhesion de cd11/cd18
WO2000035864A1 (fr) * 1998-12-16 2000-06-22 Bayer Aktiengesellschaft Nouveaux composes de biphenyle et d'analogues de biphenyle utilises en tant qu'antagonistes d'integrines
GB2354440A (en) * 1999-07-20 2001-03-28 Merck & Co Inc Aryl amides as cell adhesion inhibitors
WO2001021584A1 (fr) * 1999-09-24 2001-03-29 Genentech, Inc. Derives de tyrosine
US6313308B1 (en) 1999-03-19 2001-11-06 Bristol-Myers Squibb Company Methods for the preparation of biphenyl isoxazole sulfonamides
US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6353099B1 (en) 1999-08-20 2002-03-05 Merck & Co., Inc. Substituted ureas as cell adhesion inhibitors
WO2001058852A3 (fr) * 2000-02-11 2002-03-14 Dompe Spa Amides servant a inhiber la chimiotaxie des neutrophiles associee a l'il-8
US6380387B1 (en) 1999-12-06 2002-04-30 Hoffmann-La Roche Inc. 4-Pyrimidinyl-n-acyl-l phenylalanines
US6388084B1 (en) 1999-12-06 2002-05-14 Hoffmann-La Roche Inc. 4-pyridinyl-n-acyl-l-phenylalanines
WO2002018320A3 (fr) * 2000-08-31 2002-06-06 Tanabe Seiyaku Co Inhibiteurs de l'adhesion cellulaire induite par alpha 4
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6420418B1 (en) 1999-08-16 2002-07-16 Merck & Co., Inc. Heterocycle amides as cell adhesion inhibitors
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
US6469025B1 (en) 2000-08-02 2002-10-22 Celltech R&D Ltd. 3-substituted isoquinolin-1-yl derivatives
WO2003010135A1 (fr) * 2001-07-26 2003-02-06 Ajinomoto Co., Inc. Nouveaux derives de l'acide phenylpropionique
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6521626B1 (en) * 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6579889B2 (en) 2000-06-22 2003-06-17 Merck & Co., Inc. Substituted isonipecotyl derivatives as inhibitors of cell adhesion
US6610700B2 (en) 2000-04-17 2003-08-26 Celltech R & D Limited Enamine derivatives
WO2003072536A1 (fr) * 2002-02-28 2003-09-04 Tanabe Seiyaku Co., Ltd. Procede de preparation d'un derive de la phenylalanine, et d'un intermediaire
WO2003074478A1 (fr) * 2002-03-05 2003-09-12 Sumitomo Chemical Company, Limited Procédé de préparation de composés biaryle
US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6677360B2 (en) 1998-12-16 2004-01-13 Bayer Aktiengesellschaft Biphenyl and biphenyl-analogous compounds as integrin antagonists
US6677339B2 (en) 1998-09-28 2004-01-13 Celltech R & D Limited Phenylalanine derivatives
JPWO2002028830A1 (ja) * 2000-09-29 2004-02-12 味の素株式会社 新規フェニルアラニン誘導体
EP1394147A1 (fr) * 2001-06-04 2004-03-03 Eisai Co., Ltd. Derive de l'acide carboxylique et medicament comprenant un sel ou un ester dudit derive
WO2004069805A1 (fr) * 2003-02-10 2004-08-19 Bayer Healthcare Ag Derives de bis(hetero)aryle carboxamide destines a etre utilises en tant qu'antagonistes de la pg12
JP2004525873A (ja) * 2000-09-29 2004-08-26 ニューロジェン・コーポレーション 高親和性低分子Ｃ５ａ受容体調節物質
WO2005014532A1 (fr) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Composes aryle et heteroaryle, compositions et procedes associes
WO2004099171A3 (fr) * 2003-04-30 2005-03-31 Inst For Pharm Discovery Inc Acides amino-carboxyliques substitues
WO2005014533A3 (fr) * 2003-08-08 2005-04-07 Transtech Pharma Inc Composes aryle et heteroaryle, compositions et procedes d'utilisation
WO2004014844A3 (fr) * 2002-08-09 2005-04-28 Transtech Pharma Inc Composes aryle et heteroaryle et procedes de modulation de la coagulation
WO2005061440A1 (fr) * 2003-12-20 2005-07-07 Tanabe Seiyaku Co., Ltd. Nouveaux composes
EP1567491A2 (fr) * 2002-11-21 2005-08-31 The New York Blood Center Composes utilises pour inhiber l'infection par vih en bloquant l'entree du vih
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
US6960597B2 (en) 2000-06-30 2005-11-01 Orth-Mcneil Pharmaceutical, Inc. Aza-bridged-bicyclic amino acid derivatives as α4 integrin antagonists
US7015323B2 (en) 2003-05-20 2006-03-21 Genentech, Inc. Thiocarbamate inhibitors of alpha-4 integrins
US7067539B2 (en) 2001-02-08 2006-06-27 Schering Corporation Cannabinoid receptor ligands
US7071213B2 (en) 2001-11-14 2006-07-04 Schering Corporation Cannabinoid receptor ligands
US7115648B2 (en) 2002-03-06 2006-10-03 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
US7122567B2 (en) 2002-03-06 2006-10-17 Astrazeneca Ab Heterocyclic amide derivatives having glycogen phosphorylase inhibitory activity
US7129249B2 (en) 2002-03-06 2006-10-31 Astrazeneca Ab Heterocyclic amide derivatives as inhibitors of glycogen phoshorylase
US7138415B2 (en) 2002-03-06 2006-11-21 Astrazeneca Ab Indolamid derivatives which possess glycogenphosphorylase inhibitory activity
US7153963B2 (en) 2000-08-18 2006-12-26 Ajinomoto Co., Inc. Phenylalanine derivatives
US7160874B2 (en) 1999-11-18 2007-01-09 Ajinomoto Co., Inc. Phenylalanine derivatives
US7166636B2 (en) 2002-03-06 2007-01-23 Astrazeneca Ab Indole-amid derivatives which possess glycogen phosphorylase inhibitory activity
US7169927B2 (en) 2002-03-06 2007-01-30 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
US7217732B2 (en) 2002-06-19 2007-05-15 Schering Corporation Cannabinoid receptor agonists
US7250516B2 (en) 2001-12-13 2007-07-31 Ajinomoto Co., Inc. Phenylalanine derivatives
US7345049B2 (en) 2003-12-22 2008-03-18 Ajinomoto Co., Inc. Phenylalanine derivatives
JP2008094842A (ja) * 1999-12-06 2008-04-24 F Hoffmann La Roche Ag ４−ピリジニル−ｎ−アシル−ｌ−フェニルアラニン
US7498356B2 (en) 2004-11-18 2009-03-03 The Institutes For Pharmaceutical Discovery Llc Substituted amino carboxylic acids
WO2009052078A1 (fr) * 2007-10-19 2009-04-23 Boehringer Ingelheim International Gmbh Antagonistes de ccr10
US7544835B2 (en) 2001-04-20 2009-06-09 Eisai R&D Management Co., Ltd. Carboxylic acid derivative and salt thereof
WO2009126920A2 (fr) 2008-04-11 2009-10-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de sérum humain, et ses conjugués
US7605165B2 (en) 2002-02-20 2009-10-20 Ajinomoto Co., Inc. Phenylalanine derivatives
US7642272B2 (en) 2003-03-20 2010-01-05 Schering Corporation Cannabinoid receptor ligands
US7772249B2 (en) 2001-02-08 2010-08-10 Eisai R&D Management Co., Ltd. Imidazo[1,2-b]pyridazine compound
WO2010109115A1 (fr) * 2009-03-24 2010-09-30 Sanofi-Aventis Composés anticancéreux, leur préparation et leur application en thérapeutique
US8222286B2 (en) 2009-11-20 2012-07-17 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8263629B2 (en) 2009-05-28 2012-09-11 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
EP2510941A2 (fr) 2007-02-20 2012-10-17 Merrimack Pharmaceuticals, Inc. Procédés de traitement de la sclérose en plaques par administration d'une alpha-foetoprotéine combinée à un antagoniste de l'intégrine
US8394853B2 (en) 2009-05-28 2013-03-12 Novartis Ag Substituted aminopropionic derivatives as neprilysin inhibitors
US8431603B2 (en) 2008-04-15 2013-04-30 Eisai R&D Management Co., Ltd. 3-phenylpyrazolo[5,1-b]thiazole compounds
US8530504B2 (en) 2009-10-08 2013-09-10 Eisai R&D Management Co., Ltd. Pyrazolothiazole compound
WO2015064580A1 (fr) * 2013-10-29 2015-05-07 味の素株式会社 Dérivé de sulfonamide et son utilisation médicinale
US9102635B2 (en) 2013-02-14 2015-08-11 Novartis Ag Substituted bisphenyl butanoic acid derivatives as NEP inhibitors with improved in vivo efficacy
WO2015136468A1 (fr) 2014-03-13 2015-09-17 Prothena Biosciences Limited Polythérapie pour la sclérose en plaques
US9163040B2 (en) 2013-02-14 2015-10-20 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
US9776967B2 (en) 2013-10-14 2017-10-03 Bayer Animal Health Gmbh Carboxamide derivatives as pesticidal compounds
WO2020092375A1 (fr) * 2018-10-30 2020-05-07 Gilead Sciences, Inc. Dérivés de quinoléine utilisés en tant qu'inhibiteurs de l'intégrine alpha4bêta7
WO2020092394A1 (fr) * 2018-10-30 2020-05-07 Gilead Sciences, Inc. Dérivés d'imidazopyridine utilisés en tant qu'inhibiteurs de l'intégrine alpha4bêta7
WO2020092383A1 (fr) * 2018-10-30 2020-05-07 Gilead Sciences, Inc. Composés pour l'inhibition de l'intégrine alpha 4 bêta 7
US11104661B1 (en) 2019-10-16 2021-08-31 Morphic Therapeutic, Inc. Inhibiting human integrin (α-4) (β-7)
US11174228B2 (en) 2018-04-12 2021-11-16 Morphic Therapeutic, Inc. Antagonists of human integrin (α4)(β7)
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2266227T3 (es) * 2000-08-21 2007-03-01 Pacific Corporation Nuevos compuestos de (tio)urea y composiciones farmaceuticas que los contienen.
WO2003060078A2 (fr) * 2001-12-21 2003-07-24 X-Ceptor Therapeutics, Inc. Modulateurs heterocycliques de recepteurs nucleaires
RU2401836C2 (ru) * 2003-06-20 2010-10-20 Галдерма Ресерч энд Девелопмент, С.Н.С. НОВЫЕ СОЕДИНЕНИЯ, КОТОРЫЕ МОДУЛИРУЮТ РЕЦЕПТОРЫ ТИПА PPARγ, И ИХ ПРИМЕНЕНИЕ В КОСМЕТИЧЕСКИХ И ФАРМАЦЕВТИЧЕСКИХ КОМПОЗИЦИЯХ
US20050176755A1 (en) * 2003-10-31 2005-08-11 Dyatkin Alexey B. Aza-bridged-bicyclic amino acid derivatives as alpha4 integrin antagonists
UA81568C2 (en) * 2003-12-19 2008-01-10 Basf Ag Benzoyl-substituted phenylalanine amides, methods and intermediate products for the production thereof, herbicidal composition and method for controlling undesired plants
ZA200606557B (en) * 2004-02-06 2008-02-27 Elan Pharm Inc Methods and compositions for treating tumors and metastatic disease
EP1725538B1 (fr) * 2004-02-10 2007-08-29 Janssen Pharmaceutica N.V. Urees de pyridazinone utilisees en tant qu'antagonistes des integrines _g(a)4
US20050192279A1 (en) * 2004-02-10 2005-09-01 Kent Barbay Pyridazinones as antagonists of alpha4 integrins
JP2009516730A (ja) * 2005-11-23 2009-04-23 アストラゼネカ アクチボラグ Ｌ−アラニン誘導体
WO2007060408A2 (fr) * 2005-11-23 2007-05-31 Astrazeneca Ab Derives de l-phenylalanine
KR101360621B1 (ko) * 2005-12-29 2014-02-07 렉시컨 파마슈티컬스 인코퍼레이티드 다환식 아미노산 유도체 및 그의 사용 방법
WO2007087148A1 (fr) * 2006-01-13 2007-08-02 Transtech Pharma, Inc. Formes cristallines d'acide 3-biphényl-4-yl-(2s)-[(4'-trifluorométhyl-biphényl-4-carbonyl)-amino]-propionique, et procédés d'utilisation
EP1998612A4 (fr) * 2006-01-25 2010-11-24 Synta Pharmaceuticals Corp Composés biaryle substitués destinés à des utilisations contre des inflammations et des troubles immunitaires
AR059224A1 (es) * 2006-01-31 2008-03-19 Jerini Ag Compuestos para la inhibicion de integrinas y uso de estas
TW200811164A (en) * 2006-05-12 2008-03-01 Jerini Ag New heterocyclic compounds for the inhibition of integrins and use thereof
TW200835502A (en) 2006-12-26 2008-09-01 Daiichi Sankyo Co Ltd Thiazepine derivatives
WO2008093065A1 (fr) * 2007-01-29 2008-08-07 Astrazeneca Ab Dérivés de l-alanine utilisés comme antagonistes d'alpha-5 bêta-l
WO2008125811A1 (fr) * 2007-04-11 2008-10-23 Astrazeneca Ab DÉRIVÉS DE N-[HÉTÉROARYLCARBONYL]-S-THIÉNYL-L-ALANINE EN TANT QU'ANTAGONISTES DE L'INTÉGRINE α5β1
CA2691003A1 (fr) * 2007-06-26 2008-12-31 Lexicon Pharmaceuticals, Inc. Procedes de traitement de maladies et de troubles vehicules par la serotonine
KR20100046189A (ko) 2007-07-11 2010-05-06 렉시컨 파마슈티컬스 인코퍼레이티드 폐고혈압 및 관련 질환 및 장애의 치료를 위한 방법 및 조성물
KR101814041B1 (ko) * 2011-01-21 2018-01-02 가부시기가이샤 닛뽕쇼꾸바이 이온성 화합물, 그 제조방법, 및, 이것을 사용한 전해액, 및, 축전 디바이스
EP3008056B8 (fr) * 2013-06-11 2021-03-03 Receptos Llc Nouveaux modulateurs du récepteur glp-1
WO2018085578A1 (fr) * 2016-11-02 2018-05-11 Saint Louis University Inhibiteurs de l'intégrine en combinaison avec un agent qui interagit avec un récepteur de chimiokine
CN110845348A (zh) * 2019-12-10 2020-02-28 苏州国匡医药科技有限公司 一种arv-110中间体的制备方法
CN116924924A (zh) * 2023-07-24 2023-10-24 山东创新药物研发有限公司 一种丁卡因的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022966A1 (fr) * 1995-01-23 1996-08-01 Biogen, Inc. Inhibiteurs de l'adherence cellulaire
WO1999010312A1 (fr) * 1997-08-22 1999-03-04 F. Hoffmann-La Roche Ag Derives de n-alcanoylphenilalanine

Family Cites Families (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3508251A1 (de) 1985-03-08 1986-09-11 Merck Patent Gmbh, 6100 Darmstadt Dipeptide
GB8625941D0 (en) * 1986-10-30 1986-12-03 Sandoz Ltd Substituted alpha-amino acids
NZ228855A (en) 1988-04-25 1992-08-26 Hoffmann La Roche Tyrosine analogues and peptides containing them especially cholecystokinin (cck) analogues
JP2868914B2 (ja) 1991-03-04 1999-03-10 日本ケミファ株式会社 α−アミノ酸誘導体
US5294632A (en) * 1991-05-01 1994-03-15 Ciba-Geigy Corporation Phosphono/biaryl substituted dipetide derivatives
US5455260A (en) 1993-05-21 1995-10-03 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aliphatic amino bis-aryl squalene synthase inhibitors
JPH09504302A (ja) 1993-11-01 1997-04-28 日本チバガイギー株式会社 エンドセリン・レセプター・アンタゴニスト
US5432186A (en) * 1993-11-16 1995-07-11 Ciba-Geigy Corporation Cyclic amino acid derivatives
IL112759A0 (en) 1994-02-25 1995-05-26 Khepri Pharmaceuticals Inc Novel cysteine protease inhibitors
CN1145075A (zh) 1994-03-28 1997-03-12 贾帕特有限公司 内皮素受体拮抗剂
WO1996018606A1 (fr) * 1994-12-14 1996-06-20 Santen Pharmaceutical Co., Ltd. Nouveaux derives 1,3-dialkyluree
WO1996033170A1 (fr) 1995-04-21 1996-10-24 Novarits Ag Amides de n-aroylaminoacide utilises en tant qu'inhibiteurs d'endotheline
GB9518553D0 (en) * 1995-09-11 1995-11-08 Fujisawa Pharmaceutical Co New urea derivatives processes for the preparation thereof and pharmaceutical composition comprising the same
JPH0987291A (ja) 1995-09-26 1997-03-31 Wakamoto Pharmaceut Co Ltd 新規なアラニン誘導体
AU7130296A (en) 1995-09-28 1997-04-17 Ciba-Geigy Japan Limited Antagonists of endothelin receptors
IT1277737B1 (it) 1995-12-28 1997-11-12 Zambon Spa Derivati tiolici ad attivita' inibitrice delle metallopeptidasi
FR2745571B1 (fr) * 1996-03-04 1998-06-19 Inst Nat Sante Rech Med Nouveaux derives soufres comportant une liaison amide, leur procede de preparation, leur application a titre de medicaments, et les compositions pharmaceutiques les renfermant
DE69705838T2 (de) 1996-04-24 2002-04-11 Medivir Uk Ltd., Cambridge Substrate und inhibitoren von proteolytischen enzymen
CA2291762A1 (fr) 1997-05-29 1998-12-03 Merck & Co., Inc. Acide biarylalcanoique utilise en tant qu'inhibiteur de l'adhesion cellulaire
WO1998053814A1 (fr) 1997-05-29 1998-12-03 Merck & Co., Inc. Composes d'amide heterocycliques utilises en tant qu'inhibiteurs de l'adhesion cellulaire
AU728435B2 (en) 1997-05-29 2001-01-11 Merck & Co., Inc. Sulfonamides as cell adhesion inhibitors
US6291511B1 (en) * 1997-05-29 2001-09-18 Merck & Co., Inc. Biarylalkanoic acids as cell adhesion inhibitors
AU7667498A (en) 1997-05-30 1998-12-30 Celltech Therapeutics Limited Anti-inflammatory tyrosine derivatives
WO1998058950A1 (fr) 1997-06-20 1998-12-30 Novo Nordisk A/S Composes ayant des proprietes de liberation de l'hormone de croissance
PT991619E (pt) 1997-06-23 2004-02-27 Upjohn Co Inibidores da adesao celular mediada pela alfa4beta1
ZA986729B (en) 1997-07-29 1999-02-02 Warner Lambert Co Irreversible inhibitors of tyrosine kinases
PL338457A1 (en) 1997-07-31 2000-11-06 Elan Pharm Inc Sulphonylated dipeptidic compounds capable to inhibit adhesion of leucocytes through the mediation of vla-4
JP2001512137A (ja) 1997-07-31 2001-08-21 エラン・ファーマシューティカルズ・インコーポレーテッド Ｖｌａ−４により媒介される白血球の付着を阻害するジペプチド化合物
PL338510A1 (en) 1997-07-31 2000-11-06 Elan Pharm Inc Benzyl compounds inhinbiting the adhesion of leucocytes occurring through the mediation of vla-4
IL133641A0 (en) 1997-07-31 2001-04-30 Elan Pharm Inc Compounds which inhibit leukocyte adhesion mediated by vla-4
JP2001512134A (ja) 1997-07-31 2001-08-21 エラン・ファーマシューティカルズ・インコーポレーテッド Ｖｌａ−４仲介性白血球付着を阻害する置換フェニルアラニン型化合物
PL338373A1 (en) 1997-07-31 2000-10-23 Elan Pharm Inc Dipeptide and its affinite compounds inhibiting adhesion of leucocytes occurring through mediation of vla-4
AR016133A1 (es) 1997-07-31 2001-06-20 Wyeth Corp Compuesto de carbamiloxi que inhiben la adhesion de leucocitos mediada por vla-4, compuestos que son prodrogas de dichos compuestos, composicionfarmaceutica, metodo para fijar vla-4 a una muestra biologica, metodo para el tratamiento de una condicion inflamatoria
EP1001974B1 (fr) 1997-07-31 2006-05-24 Elan Pharmaceuticals, Inc. Composes de type 4-amino-phenylalanine inhibant une adhesion de leucocytes regulee par vla-4
AU742928C (en) 1997-08-22 2003-02-20 F. Hoffmann-La Roche Ag N-alkanoylphenylalanine derivatives
AU1361499A (en) * 1997-10-21 1999-05-10 Merck & Co., Inc. Azapeptide acids as cell adhesion inhibitors
US6069163A (en) * 1997-10-21 2000-05-30 Merck & Co., Inc. Azapeptide acids as cell adhesion inhibitors
US6191171B1 (en) 1997-11-20 2001-02-20 Merck & Co., Inc. Para-aminomethylaryl carboxamide derivatives
WO1999026923A1 (fr) 1997-11-20 1999-06-03 Merck & Co., Inc. Derives de carboxamide de para-aminomethylaryl
AU1463499A (en) 1997-11-21 1999-06-15 Merck & Co., Inc. Substituted pyrrole derivatives as cell adhesion inhibitors
CA2309338A1 (fr) 1997-11-24 1999-06-03 Merck & Co., Inc. Derives d'acide amine cycliques utilises comme inhibiteurs de l'adhesion cellulaire
CA2309341A1 (fr) 1997-11-24 1999-06-03 Merck & Co., Inc. Derives d'alanine-.beta. agissant en tant qu'inhibiteurs de l'adhesion cellulaire
US6197794B1 (en) 1998-01-08 2001-03-06 Celltech Therapeutics Limited Phenylalanine derivatives
US6329372B1 (en) 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
AU3260399A (en) 1998-02-26 1999-09-15 Celltech Therapeutics Limited Phenylalanine derivatives as inhibitors of alpha4 integrins
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
GB9811159D0 (en) 1998-05-22 1998-07-22 Celltech Therapeutics Ltd Chemical compounds
GB9812088D0 (en) 1998-06-05 1998-08-05 Celltech Therapeutics Ltd Chemical compounds
AU8059598A (en) 1998-06-11 1999-12-30 Merck & Co., Inc. Heterocyclic amide compounds as cell adhesion inhibitors
TW591026B (en) 1998-06-23 2004-06-11 Upjohn Co Inhibitors of alpha4beta1 mediated cell adhesion
DK1144365T3 (da) 1998-12-22 2004-06-28 Upjohn Co Inhibitorer af alfa4beta1-medieret celleadhæsion

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022966A1 (fr) * 1995-01-23 1996-08-01 Biogen, Inc. Inhibiteurs de l'adherence cellulaire
WO1999010312A1 (fr) * 1997-08-22 1999-03-04 F. Hoffmann-La Roche Ag Derives de n-alcanoylphenilalanine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 65, no. 10, 7 November 1966, Columbus, Ohio, US; abstract no. 15302d, S. V. SOKOLOV ET AL.: "Derivaives of 1-phenyl-2,5-bis(chlormethyl)pyrrolidine" column 2; XP002101493 *
ZH. ORGAN. KHIM., vol. 2, no. 6, 1966, pages 1088 - 1092 *

Cited By (175)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6521626B1 (en) * 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
WO1999049856A3 (fr) * 1998-03-27 1999-11-18 Genentech Inc Antagonistes destines au traitement de troubles induits par le recepteur d'adhesion de cd11/cd18
EA007852B1 (ru) * 1998-03-27 2007-02-27 Джинентех, Инк. Соединения для лечения расстройств, опосредованных рецепторами адгезии cd11/cd18
US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
US6677339B2 (en) 1998-09-28 2004-01-13 Celltech R & D Limited Phenylalanine derivatives
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
US7094911B2 (en) 1998-12-16 2006-08-22 Bayer Aktiengesellschaft Biphenyl and biphenyl-analogous compounds as integrin antagonists
WO2000035864A1 (fr) * 1998-12-16 2000-06-22 Bayer Aktiengesellschaft Nouveaux composes de biphenyle et d'analogues de biphenyle utilises en tant qu'antagonistes d'integrines
US6677360B2 (en) 1998-12-16 2004-01-13 Bayer Aktiengesellschaft Biphenyl and biphenyl-analogous compounds as integrin antagonists
US6313308B1 (en) 1999-03-19 2001-11-06 Bristol-Myers Squibb Company Methods for the preparation of biphenyl isoxazole sulfonamides
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
GB2354440A (en) * 1999-07-20 2001-03-28 Merck & Co Inc Aryl amides as cell adhesion inhibitors
US6420418B1 (en) 1999-08-16 2002-07-16 Merck & Co., Inc. Heterocycle amides as cell adhesion inhibitors
US6353099B1 (en) 1999-08-20 2002-03-05 Merck & Co., Inc. Substituted ureas as cell adhesion inhibitors
US7595399B2 (en) 1999-09-24 2009-09-29 Genentech, Inc. Tyrosine derivatives
WO2001021584A1 (fr) * 1999-09-24 2001-03-29 Genentech, Inc. Derives de tyrosine
AU780385B2 (en) * 1999-09-24 2005-03-17 Genentech Inc. Tyrosine derivatives
JP2003509488A (ja) * 1999-09-24 2003-03-11 ジェネンテック・インコーポレーテッド チロシン誘導体
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
US7160874B2 (en) 1999-11-18 2007-01-09 Ajinomoto Co., Inc. Phenylalanine derivatives
US6388084B1 (en) 1999-12-06 2002-05-14 Hoffmann-La Roche Inc. 4-pyridinyl-n-acyl-l-phenylalanines
JP2008094842A (ja) * 1999-12-06 2008-04-24 F Hoffmann La Roche Ag ４−ピリジニル−ｎ−アシル−ｌ−フェニルアラニン
US6916933B2 (en) 1999-12-06 2005-07-12 Hoffman-La Roche Inc. 4-pyridinyl-n-acyl-l-phenylalanines
US6380387B1 (en) 1999-12-06 2002-04-30 Hoffmann-La Roche Inc. 4-Pyrimidinyl-n-acyl-l phenylalanines
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6668527B2 (en) 1999-12-28 2003-12-30 Pfizer Inc. Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6903128B2 (en) 1999-12-28 2005-06-07 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
AU2001244125B2 (en) * 2000-02-11 2006-11-09 Dompe' Farmaceutici S.P.A. Amides, useful in the inhibition of IL-8-induced chemotaxis of neutrophils
RU2273630C2 (ru) * 2000-02-11 2006-04-10 Домпе С.П.А. (r)-2-арилпропионамиды, полезные при ингибировании ил-8-индуцированного хемотаксиса нейтрофилов, способ и промежуточные соединения для их получения, фармацевтическая композиция, ингибирующая хемотаксис нейтрофилов, индуцированный интерлейкином-8
US7705050B2 (en) 2000-02-11 2010-04-27 Janete Peloia Barroso Gandolfi, legal representative Amides, useful in the inhibition of IL-8-induced chemotaxis of neutrophils
CZ302945B6 (cs) * 2000-02-11 2012-01-25 Dompé Pha.R.Ma S.P.A. (R)-enantiomery amidu kyseliny 2-arylpropionové a farmaceutické smesi s jejich obsahem
WO2001058852A3 (fr) * 2000-02-11 2002-03-14 Dompe Spa Amides servant a inhiber la chimiotaxie des neutrophiles associee a l'il-8
US6610700B2 (en) 2000-04-17 2003-08-26 Celltech R & D Limited Enamine derivatives
US6780874B2 (en) 2000-04-17 2004-08-24 Celltech R & D Limited Enamine derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6579889B2 (en) 2000-06-22 2003-06-17 Merck & Co., Inc. Substituted isonipecotyl derivatives as inhibitors of cell adhesion
US6960597B2 (en) 2000-06-30 2005-11-01 Orth-Mcneil Pharmaceutical, Inc. Aza-bridged-bicyclic amino acid derivatives as α4 integrin antagonists
US6469025B1 (en) 2000-08-02 2002-10-22 Celltech R&D Ltd. 3-substituted isoquinolin-1-yl derivatives
US7153963B2 (en) 2000-08-18 2006-12-26 Ajinomoto Co., Inc. Phenylalanine derivatives
US7872125B2 (en) 2000-08-18 2011-01-18 Ajinomoto Co., Inc. Phenylalanine derivatives
US8426588B2 (en) 2000-08-18 2013-04-23 Ajinomoto Co, Inc. Phenylalanine derivatives
US8222405B2 (en) 2000-08-18 2012-07-17 Ajinomoto Co., Inc. Phenylalanine derivatives
US7026501B2 (en) 2000-08-31 2006-04-11 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US7456217B2 (en) 2000-08-31 2008-11-25 Mitsubishi Tanabe Pharma Corporation Inhibitors of alpha4 mediated cell adhesion
CZ303460B6 (cs) * 2000-08-31 2012-09-26 Mitsubishi Tanabe Pharma Corporation Derivát fenylalaninu jako inhibitor alfa4 zprostredkované bunecné adheze, farmaceutický prostredek jej obsahující a jeho použití
US8501809B2 (en) 2000-08-31 2013-08-06 Mitsubishi Tanabe Pharma Corporation Inhibitors of α4 mediated cell adhesion
US7671090B2 (en) 2000-08-31 2010-03-02 Mitsubishi Tanabe Pharma Corporation Inhibitors of α4 mediated cell adhesion
RU2250895C2 (ru) * 2000-08-31 2005-04-27 Танабе Сейяку Ко., Лтд. ИНГИБИТОРЫ КЛЕТОЧНОЙ АДГЕЗИИ, ОПОСРЕДОВАННОЙ α4-ИНТЕГРИНАМИ
AU2001286778B2 (en) * 2000-08-31 2005-02-10 Tanabe Seiyaku Co., Ltd. Inhibitors of alpha4 mediated cell adhesion
WO2002018320A3 (fr) * 2000-08-31 2002-06-06 Tanabe Seiyaku Co Inhibiteurs de l'adhesion cellulaire induite par alpha 4
US7872151B2 (en) 2000-08-31 2011-01-18 Mitsubishi Tanabe Pharma Corporation Inhibitors of α4 mediated cell adhesion
US7452905B2 (en) 2000-09-29 2008-11-18 Ajinomoto Co., Inc. Phenylalanine derivatives
JPWO2002028830A1 (ja) * 2000-09-29 2004-02-12 味の素株式会社 新規フェニルアラニン誘導体
US7759388B2 (en) 2000-09-29 2010-07-20 Ajinomoto Co., Inc. Phenylalanine derivatives
JP2004525873A (ja) * 2000-09-29 2004-08-26 ニューロジェン・コーポレーション 高親和性低分子Ｃ５ａ受容体調節物質
JP4895067B2 (ja) * 2000-09-29 2012-03-14 味の素株式会社 新規フェニルアラニン誘導体
US7067539B2 (en) 2001-02-08 2006-06-27 Schering Corporation Cannabinoid receptor ligands
US7772249B2 (en) 2001-02-08 2010-08-10 Eisai R&D Management Co., Ltd. Imidazo[1,2-b]pyridazine compound
US7544835B2 (en) 2001-04-20 2009-06-09 Eisai R&D Management Co., Ltd. Carboxylic acid derivative and salt thereof
US7687664B2 (en) 2001-06-04 2010-03-30 Eisai R&D Management Co., Ltd. Carboxylic acid derivative, a salt thereof or an ester of them, and medicament comprising it
EP1394147A1 (fr) * 2001-06-04 2004-03-03 Eisai Co., Ltd. Derive de l'acide carboxylique et medicament comprenant un sel ou un ester dudit derive
EP1394147A4 (fr) * 2001-06-04 2007-10-24 Eisai R&D Man Co Ltd Derive de l'acide carboxylique et medicament comprenant un sel ou un ester dudit derive
JPWO2002098840A1 (ja) * 2001-06-04 2004-09-16 エーザイ株式会社 カルボン酸誘導体及びその塩もしくはそのエステルからなる医薬
WO2003010135A1 (fr) * 2001-07-26 2003-02-06 Ajinomoto Co., Inc. Nouveaux derives de l'acide phenylpropionique
US7193108B2 (en) 2001-07-26 2007-03-20 Ajinomoto Co., Inc. Phenylpropionic acid derivatives
US7645774B2 (en) 2001-11-14 2010-01-12 Schering Corporation Cannabinoid receptor ligands
US7071213B2 (en) 2001-11-14 2006-07-04 Schering Corporation Cannabinoid receptor ligands
US7250516B2 (en) 2001-12-13 2007-07-31 Ajinomoto Co., Inc. Phenylalanine derivatives
US7884204B2 (en) 2001-12-13 2011-02-08 Ajinomoto Co., Inc. Phenylalanine derivatives
US7605165B2 (en) 2002-02-20 2009-10-20 Ajinomoto Co., Inc. Phenylalanine derivatives
RU2280641C2 (ru) * 2002-02-28 2006-07-27 Танабе Сейяку Ко., Лтд Способ получения производных фенилаланина и их полупродуктов
AU2003208618B2 (en) * 2002-02-28 2008-06-19 Mitsubishi Tanabe Pharma Corporation A process for preparing a phenylalanine derivative and intermediates thereof
WO2003072536A1 (fr) * 2002-02-28 2003-09-04 Tanabe Seiyaku Co., Ltd. Procede de preparation d'un derive de la phenylalanine, et d'un intermediaire
EP1481967A4 (fr) * 2002-03-05 2007-01-31 Sumitomo Chemical Co Procede de preparation de composes biaryle
EP1481967A1 (fr) * 2002-03-05 2004-12-01 Sumitomo Chemical Company, Limited Procede de preparation de composes biaryle
US7714157B2 (en) 2002-03-05 2010-05-11 Sumitomo Chemical Company, Limited Process for preparing a biaryl compound
US7271280B2 (en) 2002-03-05 2007-09-18 Sumitomo Chemical Company, Limited Process for preparing a biaryl compound
WO2003074478A1 (fr) * 2002-03-05 2003-09-12 Sumitomo Chemical Company, Limited Procédé de préparation de composés biaryle
US7169927B2 (en) 2002-03-06 2007-01-30 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
US7332515B2 (en) 2002-03-06 2008-02-19 Astrazeneca Ab Indole-amid derivatives which possess glycogen phosphorylase inhibitory activity
US7166636B2 (en) 2002-03-06 2007-01-23 Astrazeneca Ab Indole-amid derivatives which possess glycogen phosphorylase inhibitory activity
US7129249B2 (en) 2002-03-06 2006-10-31 Astrazeneca Ab Heterocyclic amide derivatives as inhibitors of glycogen phoshorylase
US7122567B2 (en) 2002-03-06 2006-10-17 Astrazeneca Ab Heterocyclic amide derivatives having glycogen phosphorylase inhibitory activity
US7115648B2 (en) 2002-03-06 2006-10-03 Astrazeneca Ab Indole-amide derivatives and their use as glycogen phosphorylase inhibitors
US7138415B2 (en) 2002-03-06 2006-11-21 Astrazeneca Ab Indolamid derivatives which possess glycogenphosphorylase inhibitory activity
US7217732B2 (en) 2002-06-19 2007-05-15 Schering Corporation Cannabinoid receptor agonists
WO2004014844A3 (fr) * 2002-08-09 2005-04-28 Transtech Pharma Inc Composes aryle et heteroaryle et procedes de modulation de la coagulation
US7122580B2 (en) 2002-08-09 2006-10-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds and methods to modulate coagulation
EP1567491A4 (fr) * 2002-11-21 2007-09-19 New York Blood Ct Inc Composes utilises pour inhiber l'infection par vih en bloquant l'entree du vih
EP1567491A2 (fr) * 2002-11-21 2005-08-31 The New York Blood Center Composes utilises pour inhiber l'infection par vih en bloquant l'entree du vih
WO2004069805A1 (fr) * 2003-02-10 2004-08-19 Bayer Healthcare Ag Derives de bis(hetero)aryle carboxamide destines a etre utilises en tant qu'antagonistes de la pg12
US7642272B2 (en) 2003-03-20 2010-01-05 Schering Corporation Cannabinoid receptor ligands
WO2004099171A3 (fr) * 2003-04-30 2005-03-31 Inst For Pharm Discovery Inc Acides amino-carboxyliques substitues
AU2004236247B2 (en) * 2003-04-30 2008-11-06 The Institutes For Pharmaceutical Discovery, Llc Substituted amino carboxylic acids as inhibitors of protein tyrosine phosphatase-1 B
US7358248B2 (en) 2003-04-30 2008-04-15 The Institute For Pharmaceutical Discovery Llc Substituted amino carboxylic acids
US7015323B2 (en) 2003-05-20 2006-03-21 Genentech, Inc. Thiocarbamate inhibitors of alpha-4 integrins
US7166600B2 (en) 2003-05-20 2007-01-23 Genentech, Inc. Thiocarbamate inhibitors of alpha-4 integrins
WO2005014532A1 (fr) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Composes aryle et heteroaryle, compositions et procedes associes
WO2005014534A1 (fr) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Composes aryle et heteroaryle, compositions, et methodes d'utilisation
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
US7544699B2 (en) 2003-08-08 2009-06-09 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use
US7459472B2 (en) 2003-08-08 2008-12-02 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use
WO2005014533A3 (fr) * 2003-08-08 2005-04-07 Transtech Pharma Inc Composes aryle et heteroaryle, compositions et procedes d'utilisation
US7501538B2 (en) 2003-08-08 2009-03-10 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions and methods of use
AU2004303687B2 (en) * 2003-12-20 2007-12-13 Mitsubishi Tanabe Pharma Corporation Novel compounds
WO2005061440A1 (fr) * 2003-12-20 2005-07-07 Tanabe Seiyaku Co., Ltd. Nouveaux composes
US7345049B2 (en) 2003-12-22 2008-03-18 Ajinomoto Co., Inc. Phenylalanine derivatives
EP2803667A1 (fr) 2003-12-22 2014-11-19 Ajinomoto Co., Inc. Dérivés de phenylalanine
EP2615087A2 (fr) 2003-12-22 2013-07-17 Ajinomoto Co., Inc. Dérivés de phénylalanine
US8309561B2 (en) 2003-12-22 2012-11-13 Ajinomoto Co., Inc. Phenylalanine derivatives
US7498356B2 (en) 2004-11-18 2009-03-03 The Institutes For Pharmaceutical Discovery Llc Substituted amino carboxylic acids
EP2510941A2 (fr) 2007-02-20 2012-10-17 Merrimack Pharmaceuticals, Inc. Procédés de traitement de la sclérose en plaques par administration d'une alpha-foetoprotéine combinée à un antagoniste de l'intégrine
WO2009052078A1 (fr) * 2007-10-19 2009-04-23 Boehringer Ingelheim International Gmbh Antagonistes de ccr10
US8299123B2 (en) 2007-10-19 2012-10-30 Boehringer Ingelheim International Gmbh CCR10 antagonists
EP2860260A1 (fr) 2008-04-11 2015-04-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de sérum humain et de leurs conjugués
WO2009126920A2 (fr) 2008-04-11 2009-10-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de sérum humain, et ses conjugués
US8431603B2 (en) 2008-04-15 2013-04-30 Eisai R&D Management Co., Ltd. 3-phenylpyrazolo[5,1-b]thiazole compounds
FR2943671A1 (fr) * 2009-03-24 2010-10-01 Sanofi Aventis Composes anticancereux,leur preparation et leur application en therapeutique
WO2010109115A1 (fr) * 2009-03-24 2010-09-30 Sanofi-Aventis Composés anticancéreux, leur préparation et leur application en thérapeutique
US8394853B2 (en) 2009-05-28 2013-03-12 Novartis Ag Substituted aminopropionic derivatives as neprilysin inhibitors
US8263629B2 (en) 2009-05-28 2012-09-11 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
US9603819B2 (en) 2009-05-28 2017-03-28 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
US9006249B2 (en) 2009-05-28 2015-04-14 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
US8530504B2 (en) 2009-10-08 2013-09-10 Eisai R&D Management Co., Ltd. Pyrazolothiazole compound
US8377978B2 (en) 2009-11-20 2013-02-19 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8877786B2 (en) 2009-11-20 2014-11-04 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8642635B2 (en) 2009-11-20 2014-02-04 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8222286B2 (en) 2009-11-20 2012-07-17 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US9163040B2 (en) 2013-02-14 2015-10-20 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
US9102635B2 (en) 2013-02-14 2015-08-11 Novartis Ag Substituted bisphenyl butanoic acid derivatives as NEP inhibitors with improved in vivo efficacy
US9480693B2 (en) 2013-02-14 2016-11-01 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
US10112963B2 (en) 2013-02-14 2018-10-30 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
US9776967B2 (en) 2013-10-14 2017-10-03 Bayer Animal Health Gmbh Carboxamide derivatives as pesticidal compounds
WO2015064580A1 (fr) * 2013-10-29 2015-05-07 味の素株式会社 Dérivé de sulfonamide et son utilisation médicinale
US9822110B2 (en) 2013-10-29 2017-11-21 Ea Pharma Co., Ltd. Sulfonamide derivative and pharmaceutical use thereof
KR101806103B1 (ko) 2013-10-29 2017-12-07 이에이 파마 가부시키가이샤 설폰아미드 유도체 및 이의 의약 용도
RU2667520C2 (ru) * 2013-10-29 2018-09-21 ЕА Фарма Ко., Лтд. Производное сульфонамида и его применение в медицине
RU2667520C9 (ru) * 2013-10-29 2019-03-05 ЕА Фарма Ко., Лтд. Производное сульфонамида и его применение в медицине
WO2015136468A1 (fr) 2014-03-13 2015-09-17 Prothena Biosciences Limited Polythérapie pour la sclérose en plaques
US11174228B2 (en) 2018-04-12 2021-11-16 Morphic Therapeutic, Inc. Antagonists of human integrin (α4)(β7)
US12221416B2 (en) 2018-04-12 2025-02-11 Morphic Therapeutic, Inc. Antagonists of human integrin α4β7
AU2019373240B2 (en) * 2018-10-30 2023-04-20 Gilead Sciences, Inc. Quinoline derivatives as alpha4beta7 integrin inhibitors
TWI800691B (zh) * 2018-10-30 2023-05-01 美商基利科學股份有限公司 抑制α4β7整合素的化合物
CN112969687A (zh) * 2018-10-30 2021-06-15 吉利德科学公司 作为α4β7整合素抑制剂的喹啉衍生物
CN112996786A (zh) * 2018-10-30 2021-06-18 吉利德科学公司 用于抑制α4β7整合素的化合物
KR20210086672A (ko) * 2018-10-30 2021-07-08 길리애드 사이언시즈, 인코포레이티드 알파4베타7 인테그린의 억제를 위한 화합물
KR20210087480A (ko) * 2018-10-30 2021-07-12 길리애드 사이언시즈, 인코포레이티드 알파4베타7 인테그린 억제제로서의 이미다조피리딘 유도체
KR20210087961A (ko) * 2018-10-30 2021-07-13 길리애드 사이언시즈, 인코포레이티드 알파4베타7 인테그린 억제제로서의 퀴놀린 유도체
TWI734240B (zh) * 2018-10-30 2021-07-21 美商基利科學股份有限公司 喹啉衍生物
CN112969700A (zh) * 2018-10-30 2021-06-15 吉利德科学公司 作为α4β7整合素抑制剂的咪唑并吡啶衍生物
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
WO2020092383A1 (fr) * 2018-10-30 2020-05-07 Gilead Sciences, Inc. Composés pour l'inhibition de l'intégrine alpha 4 bêta 7
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
WO2020092375A1 (fr) * 2018-10-30 2020-05-07 Gilead Sciences, Inc. Dérivés de quinoléine utilisés en tant qu'inhibiteurs de l'intégrine alpha4bêta7
TWI777100B (zh) * 2018-10-30 2022-09-11 美商基利科學股份有限公司 抑制α4β7整合素的化合物
AU2019373244B2 (en) * 2018-10-30 2022-05-26 Gilead Sciences, Inc. Imidazopyridine derivatives as alpha4beta7 integrin inhibitors
CN112969687B (zh) * 2018-10-30 2024-08-23 吉利德科学公司 作为α4β7整合素抑制剂的喹啉衍生物
WO2020092394A1 (fr) * 2018-10-30 2020-05-07 Gilead Sciences, Inc. Dérivés d'imidazopyridine utilisés en tant qu'inhibiteurs de l'intégrine alpha4bêta7
IL282545B2 (en) * 2018-10-30 2025-04-01 Gilead Sciences Inc Quinoline derivatives as alpha4beta7 integrin inhibitors
AU2019373242B2 (en) * 2018-10-30 2023-07-13 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
KR102630416B1 (ko) 2018-10-30 2024-02-01 길리애드 사이언시즈, 인코포레이티드 알파4베타7 인테그린 억제제로서의 퀴놀린 유도체
KR102641718B1 (ko) 2018-10-30 2024-02-29 길리애드 사이언시즈, 인코포레이티드 알파4베타7 인테그린 억제제로서의 이미다조피리딘 유도체
KR102652797B1 (ko) 2018-10-30 2024-04-02 길리애드 사이언시즈, 인코포레이티드 알파4베타7 인테그린의 억제를 위한 화합물
TWI843952B (zh) * 2018-10-30 2024-06-01 美商基利科學股份有限公司 喹啉衍生物
US12053462B2 (en) 2018-10-30 2024-08-06 Gilead Sciences, Inc. Quinoline derivatives
CN112996786B (zh) * 2018-10-30 2024-08-20 吉利德科学公司 用于抑制α4β7整合素的化合物
CN112969700B (zh) * 2018-10-30 2024-08-20 吉利德科学公司 作为α4β7整合素抑制剂的咪唑并吡啶衍生物
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin
US11104661B1 (en) 2019-10-16 2021-08-31 Morphic Therapeutic, Inc. Inhibiting human integrin (α-4) (β-7)
US11370773B1 (en) 2019-10-16 2022-06-28 Morphic Therapeutic, Inc. Inhibiting human integrin (alpha-4) (beta-7)

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US20030191118A1 (en) 2003-10-09
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DE69932032T2 (de) 2006-12-28
EP1049662B1 (fr) 2006-06-21
CN1301964C (zh) 2007-02-28
KR20010033180A (ko) 2001-04-25
IL137385A0 (en) 2001-07-24
DE69932032D1 (de) 2006-08-03
CA2318527A1 (fr) 1999-07-22
US6855843B2 (en) 2005-02-15
TW591007B (en) 2004-06-11
CY1105433T1 (el) 2010-04-28
BR9907040B1 (pt) 2010-11-30
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US6521666B1 (en) 2003-02-18
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AU749568B2 (en) 2002-06-27
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AR014448A1 (es) 2001-02-28
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IL137385A (en) 2006-08-20
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DK1049662T3 (da) 2006-10-23
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EP1049662A1 (fr) 2000-11-08
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